Neurology

First responders to the World Trade Center (WTC) attacks on Sept. 11, 2001, who have cognitive impairment show cortical thinning across multiple brain regions, including those commonly affected by Alzheimer’s disease, suggest results from the first structural neuroimaging study conducted in this population. The study clarifies that a neurodegenerative condition is present in first responders who experience cognitive impairment in midlife, which “is incredibly important to know,” said lead author Sean Clouston, PhD, of Stony Brook (N.Y.) University.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were published online in Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring.
 

Brain atrophy in midlife

During the 9/11 attack and in its aftermath, WTC responders were exposed to a range of inhaled neurotoxicants, as well as extreme psychosocial stressors. A growing number of WTC responders who are now in their 50s and early 60s are experiencing early cognitive impairment.

Using MRI, the investigators examined cortical thickness (CTX), a surrogate marker for neurodegeneration, in 99 mostly male WTC responders; 48 had cognitive impairment, and 51 did not. The age range of the participants was 45 to 65 years, a range during which cortical atrophy is uncommon in the general population, the researchers noted.

Compared with cognitively normal responders, those with cognitive impairment were found to have reductions in CTX across the whole brain and across 21 of 34 cortical regions, including frontal, temporal, and occipital lobes.

In both cognitively impaired and cognitively unimpaired WTC responders, CTX was reduced in the entorhinal and temporal cortices compared with normative data, but reductions were greater with cognitive impairment. Posttraumatic distress disorder (PTSD) status was not predictive of a reduction in CTX across groups.

Dr. Clouston said the level of reduction in CTX in many responders is similar to that commonly found in patients with dementia and may reflect early-stage dementia occurring in midlife.

Limitations of the study include the small sample size, the cross-sectional design, the unique nature of the exposure, and a lack of a non-WTC external control group.
 

‘Illuminating’ study

Keith N. Fargo, PhD, director of scientific engagement for the Alzheimer’s Association, called the findings “interesting and illuminating” but cautioned that it is not possible to show cause and effect with this type of study.

“We also don’t know when cortical thinning might have started or how quickly it might be progressing,” Dr. Fargo said in an interview.

He noted that the pattern of cortical thinning is “somewhat consistent with what we see among people who live with high levels of air pollution, which is an emerging risk factor for Alzheimer’s disease and other dementias.”

The Lancet Commission on Dementia Prevention, Intervention, and Care added air pollution to its list of modifiable risk factors for dementia, which was recently updated.

Clinicians “need to be aware that their middle-aged 9/11 first responders are at a higher risk level for cognitive impairment, as well as PTSD and depression,” Dr. Fargo said.

The study was funded by the Centers for Disease Control and Prevention and the National Institute on Aging. Dr. Clouston and Dr. Fargo have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

First responders to the World Trade Center (WTC) attacks on Sept. 11, 2001, who have cognitive impairment show cortical thinning across multiple brain regions, including those commonly affected by Alzheimer’s disease, suggest results from the first structural neuroimaging study conducted in this population. The study clarifies that a neurodegenerative condition is present in first responders who experience cognitive impairment in midlife, which “is incredibly important to know,” said lead author Sean Clouston, PhD, of Stony Brook (N.Y.) University.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were published online in Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring.
 

Brain atrophy in midlife

During the 9/11 attack and in its aftermath, WTC responders were exposed to a range of inhaled neurotoxicants, as well as extreme psychosocial stressors. A growing number of WTC responders who are now in their 50s and early 60s are experiencing early cognitive impairment.

Using MRI, the investigators examined cortical thickness (CTX), a surrogate marker for neurodegeneration, in 99 mostly male WTC responders; 48 had cognitive impairment, and 51 did not. The age range of the participants was 45 to 65 years, a range during which cortical atrophy is uncommon in the general population, the researchers noted.

Compared with cognitively normal responders, those with cognitive impairment were found to have reductions in CTX across the whole brain and across 21 of 34 cortical regions, including frontal, temporal, and occipital lobes.

In both cognitively impaired and cognitively unimpaired WTC responders, CTX was reduced in the entorhinal and temporal cortices compared with normative data, but reductions were greater with cognitive impairment. Posttraumatic distress disorder (PTSD) status was not predictive of a reduction in CTX across groups.

Dr. Clouston said the level of reduction in CTX in many responders is similar to that commonly found in patients with dementia and may reflect early-stage dementia occurring in midlife.

Limitations of the study include the small sample size, the cross-sectional design, the unique nature of the exposure, and a lack of a non-WTC external control group.
 

‘Illuminating’ study

Keith N. Fargo, PhD, director of scientific engagement for the Alzheimer’s Association, called the findings “interesting and illuminating” but cautioned that it is not possible to show cause and effect with this type of study.

“We also don’t know when cortical thinning might have started or how quickly it might be progressing,” Dr. Fargo said in an interview.

He noted that the pattern of cortical thinning is “somewhat consistent with what we see among people who live with high levels of air pollution, which is an emerging risk factor for Alzheimer’s disease and other dementias.”

The Lancet Commission on Dementia Prevention, Intervention, and Care added air pollution to its list of modifiable risk factors for dementia, which was recently updated.

Clinicians “need to be aware that their middle-aged 9/11 first responders are at a higher risk level for cognitive impairment, as well as PTSD and depression,” Dr. Fargo said.

The study was funded by the Centers for Disease Control and Prevention and the National Institute on Aging. Dr. Clouston and Dr. Fargo have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

First responders to the World Trade Center (WTC) attacks on Sept. 11, 2001, who have cognitive impairment show cortical thinning across multiple brain regions, including those commonly affected by Alzheimer’s disease, suggest results from the first structural neuroimaging study conducted in this population. The study clarifies that a neurodegenerative condition is present in first responders who experience cognitive impairment in midlife, which “is incredibly important to know,” said lead author Sean Clouston, PhD, of Stony Brook (N.Y.) University.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were published online in Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring.
 

Brain atrophy in midlife

During the 9/11 attack and in its aftermath, WTC responders were exposed to a range of inhaled neurotoxicants, as well as extreme psychosocial stressors. A growing number of WTC responders who are now in their 50s and early 60s are experiencing early cognitive impairment.

Using MRI, the investigators examined cortical thickness (CTX), a surrogate marker for neurodegeneration, in 99 mostly male WTC responders; 48 had cognitive impairment, and 51 did not. The age range of the participants was 45 to 65 years, a range during which cortical atrophy is uncommon in the general population, the researchers noted.

Compared with cognitively normal responders, those with cognitive impairment were found to have reductions in CTX across the whole brain and across 21 of 34 cortical regions, including frontal, temporal, and occipital lobes.

In both cognitively impaired and cognitively unimpaired WTC responders, CTX was reduced in the entorhinal and temporal cortices compared with normative data, but reductions were greater with cognitive impairment. Posttraumatic distress disorder (PTSD) status was not predictive of a reduction in CTX across groups.

Dr. Clouston said the level of reduction in CTX in many responders is similar to that commonly found in patients with dementia and may reflect early-stage dementia occurring in midlife.

Limitations of the study include the small sample size, the cross-sectional design, the unique nature of the exposure, and a lack of a non-WTC external control group.
 

‘Illuminating’ study

Keith N. Fargo, PhD, director of scientific engagement for the Alzheimer’s Association, called the findings “interesting and illuminating” but cautioned that it is not possible to show cause and effect with this type of study.

“We also don’t know when cortical thinning might have started or how quickly it might be progressing,” Dr. Fargo said in an interview.

He noted that the pattern of cortical thinning is “somewhat consistent with what we see among people who live with high levels of air pollution, which is an emerging risk factor for Alzheimer’s disease and other dementias.”

The Lancet Commission on Dementia Prevention, Intervention, and Care added air pollution to its list of modifiable risk factors for dementia, which was recently updated.

Clinicians “need to be aware that their middle-aged 9/11 first responders are at a higher risk level for cognitive impairment, as well as PTSD and depression,” Dr. Fargo said.

The study was funded by the Centers for Disease Control and Prevention and the National Institute on Aging. Dr. Clouston and Dr. Fargo have reported no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Background: Studies have demonstrated the increased risk for ischemic stroke in patients diagnosed with acute PE, and data support the mechanism of paradoxical embolism via PFO. However, the frequency of this phenomenon is unknown and the strength of the association between PFO and ischemic stroke in patients with PE is unclear.

This study adds to the growing body of data which supports the association of ischemic stroke with PFO and PE. Given the moderate indication for indefinite anticoagulation in patients at high risk for recurrent PE and stroke, there may be a role for screening for PFO in patients with acute PE so that they can be appropriately risk stratified.

Bottom line: The presence of ischemic stroke in patients with acute pulmonary embolism is high, and there is a strong association with PFO.

Citation: Le Moigne E et al. Patent Foramen Ovale and Ischemic Stroke in Patients With Pulmonary Embolism: A Prospective Cohort Study. Ann Intern Med. 2019;170:756-63.
 

Dr. McIntyre is a hospitalist at Ochsner Health System, New Orleans.

Background: Studies have demonstrated the increased risk for ischemic stroke in patients diagnosed with acute PE, and data support the mechanism of paradoxical embolism via PFO. However, the frequency of this phenomenon is unknown and the strength of the association between PFO and ischemic stroke in patients with PE is unclear.

This study adds to the growing body of data which supports the association of ischemic stroke with PFO and PE. Given the moderate indication for indefinite anticoagulation in patients at high risk for recurrent PE and stroke, there may be a role for screening for PFO in patients with acute PE so that they can be appropriately risk stratified.

Bottom line: The presence of ischemic stroke in patients with acute pulmonary embolism is high, and there is a strong association with PFO.

Citation: Le Moigne E et al. Patent Foramen Ovale and Ischemic Stroke in Patients With Pulmonary Embolism: A Prospective Cohort Study. Ann Intern Med. 2019;170:756-63.
 

Dr. McIntyre is a hospitalist at Ochsner Health System, New Orleans.

Background: Studies have demonstrated the increased risk for ischemic stroke in patients diagnosed with acute PE, and data support the mechanism of paradoxical embolism via PFO. However, the frequency of this phenomenon is unknown and the strength of the association between PFO and ischemic stroke in patients with PE is unclear.

This study adds to the growing body of data which supports the association of ischemic stroke with PFO and PE. Given the moderate indication for indefinite anticoagulation in patients at high risk for recurrent PE and stroke, there may be a role for screening for PFO in patients with acute PE so that they can be appropriately risk stratified.

Bottom line: The presence of ischemic stroke in patients with acute pulmonary embolism is high, and there is a strong association with PFO.

Citation: Le Moigne E et al. Patent Foramen Ovale and Ischemic Stroke in Patients With Pulmonary Embolism: A Prospective Cohort Study. Ann Intern Med. 2019;170:756-63.
 

Dr. McIntyre is a hospitalist at Ochsner Health System, New Orleans.

The cannabidiol (CBD) oral solution Epidiolex has been approved by the Food and Drug Administration for the new indication of treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age and older.

The drug was approved by the FDA in 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, as reported by Medscape Medical News.

This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. It is also the second FDA approval of a drug for the treatment of seizures associated with tuberous sclerosis complex.

CBD is a chemical component of the cannabis sativa plant, but it does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC), which is the primary psychoactive component of cannabis.

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions,” Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

“This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” Dr. Throckmorton said.

He added that the FDA is committed to supporting research on the potential medical uses of cannabis-derived products.
 

Rare genetic disease

Tuberous sclerosis complex is a rare genetic disease that causes benign tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin.

It usually affects the central nervous system and can result in a combination of symptoms, including seizures, developmental delay, and behavioral problems. The signs and symptoms of the condition, as well as the severity of symptoms, vary widely. The disease affects about 1 in 6,000 individuals.

The effectiveness of Epidiolex in the treatment of seizures associated with tuberous sclerosis complex was established in a randomized, double-blind, placebo-controlled trial in which 148 patients of a total of 224 in the study received the active drug, the FDA noted.

Results showed that for patients treated with CBD, there was a significantly greater reduction in seizure frequency during the treatment period than for patients who received placebo.

This effect was seen within 8 weeks and remained consistent throughout the 16-week treatment period.

The most common side effects that occurred in CBD-treated participants were diarrhea, elevated liver enzyme levels, decreased appetite, sleepiness, fever, and vomiting. Additional side effects that have been reported with the product include liver injury, decreased weight, anemia, and increased creatinine level.

As is true for all drugs that currently treat epilepsy, including Epidiolex, the most serious risks may include an increase in suicidal thoughts and behavior or thoughts of self-harm, the FDA reports.

Patients, their caregivers, and their families should be advised to monitor for any unusual changes in mood or behavior, such as worsening depression or suicidal thoughts or behavior. They should report behaviors of concern immediately to health care providers, the agency notes.

It also points out that Epidiolex can cause liver injury, of which most cases are generally mild. However, there is a risk for rare but more severe liver injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.

A version of this story originally appeared on Medscape.com.

The cannabidiol (CBD) oral solution Epidiolex has been approved by the Food and Drug Administration for the new indication of treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age and older.

The drug was approved by the FDA in 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, as reported by Medscape Medical News.

This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. It is also the second FDA approval of a drug for the treatment of seizures associated with tuberous sclerosis complex.

CBD is a chemical component of the cannabis sativa plant, but it does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC), which is the primary psychoactive component of cannabis.

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions,” Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

“This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” Dr. Throckmorton said.

He added that the FDA is committed to supporting research on the potential medical uses of cannabis-derived products.
 

Rare genetic disease

Tuberous sclerosis complex is a rare genetic disease that causes benign tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin.

It usually affects the central nervous system and can result in a combination of symptoms, including seizures, developmental delay, and behavioral problems. The signs and symptoms of the condition, as well as the severity of symptoms, vary widely. The disease affects about 1 in 6,000 individuals.

The effectiveness of Epidiolex in the treatment of seizures associated with tuberous sclerosis complex was established in a randomized, double-blind, placebo-controlled trial in which 148 patients of a total of 224 in the study received the active drug, the FDA noted.

Results showed that for patients treated with CBD, there was a significantly greater reduction in seizure frequency during the treatment period than for patients who received placebo.

This effect was seen within 8 weeks and remained consistent throughout the 16-week treatment period.

The most common side effects that occurred in CBD-treated participants were diarrhea, elevated liver enzyme levels, decreased appetite, sleepiness, fever, and vomiting. Additional side effects that have been reported with the product include liver injury, decreased weight, anemia, and increased creatinine level.

As is true for all drugs that currently treat epilepsy, including Epidiolex, the most serious risks may include an increase in suicidal thoughts and behavior or thoughts of self-harm, the FDA reports.

Patients, their caregivers, and their families should be advised to monitor for any unusual changes in mood or behavior, such as worsening depression or suicidal thoughts or behavior. They should report behaviors of concern immediately to health care providers, the agency notes.

It also points out that Epidiolex can cause liver injury, of which most cases are generally mild. However, there is a risk for rare but more severe liver injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.

A version of this story originally appeared on Medscape.com.

The cannabidiol (CBD) oral solution Epidiolex has been approved by the Food and Drug Administration for the new indication of treatment of seizures associated with tuberous sclerosis complex in patients 1 year of age and older.

The drug was approved by the FDA in 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, as reported by Medscape Medical News.

This is the only FDA-approved drug that contains a purified drug substance derived from cannabis. It is also the second FDA approval of a drug for the treatment of seizures associated with tuberous sclerosis complex.

CBD is a chemical component of the cannabis sativa plant, but it does not cause intoxication or euphoria (the “high”) that comes from tetrahydrocannabinol (THC), which is the primary psychoactive component of cannabis.

“The FDA continues to believe the drug approval process represents the best way to make new medicines, including any drugs derived from cannabis, available to patients in need of appropriate medical therapy such as the treatment of seizures associated with these rare conditions,” Douglas Throckmorton, MD, deputy center director for regulatory programs in the FDA’s Center for Drug Evaluation and Research, said in an agency press release.

“This paradigm ensures new therapies are safe, effective, and manufactured to a high quality that provides uniform and reliable dosing for patients,” Dr. Throckmorton said.

He added that the FDA is committed to supporting research on the potential medical uses of cannabis-derived products.
 

Rare genetic disease

Tuberous sclerosis complex is a rare genetic disease that causes benign tumors to grow in the brain and other parts of the body, such as the eyes, heart, kidneys, lungs, and skin.

It usually affects the central nervous system and can result in a combination of symptoms, including seizures, developmental delay, and behavioral problems. The signs and symptoms of the condition, as well as the severity of symptoms, vary widely. The disease affects about 1 in 6,000 individuals.

The effectiveness of Epidiolex in the treatment of seizures associated with tuberous sclerosis complex was established in a randomized, double-blind, placebo-controlled trial in which 148 patients of a total of 224 in the study received the active drug, the FDA noted.

Results showed that for patients treated with CBD, there was a significantly greater reduction in seizure frequency during the treatment period than for patients who received placebo.

This effect was seen within 8 weeks and remained consistent throughout the 16-week treatment period.

The most common side effects that occurred in CBD-treated participants were diarrhea, elevated liver enzyme levels, decreased appetite, sleepiness, fever, and vomiting. Additional side effects that have been reported with the product include liver injury, decreased weight, anemia, and increased creatinine level.

As is true for all drugs that currently treat epilepsy, including Epidiolex, the most serious risks may include an increase in suicidal thoughts and behavior or thoughts of self-harm, the FDA reports.

Patients, their caregivers, and their families should be advised to monitor for any unusual changes in mood or behavior, such as worsening depression or suicidal thoughts or behavior. They should report behaviors of concern immediately to health care providers, the agency notes.

It also points out that Epidiolex can cause liver injury, of which most cases are generally mild. However, there is a risk for rare but more severe liver injury. More severe liver injury can cause nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.

A version of this story originally appeared on Medscape.com.

Pediatric acute-onset neuropsychiatric syndrome (PANS), a rare acute onset of psychiatric symptoms, might be more common than initially thought, according to Kiki D. Chang, MD.

PANS is characterized by the National Center for Advancing Translational Sciences Genetic and Rare Diseases Information Center as a “sudden onset of obsessive-compulsive symptoms and/or severe eating restrictions, along with at least two other cognitive, behavioral, or neurological symptoms.” These symptoms can include anxiety, depression, oppositional behavior, difficulty concentrating, abnormalities in motor and sensory skills, and other somatic symptoms. The condition develops as a result of an infection that causes an autoimmune or inflammatory response in the brain, and patients tend to respond well to treatment from antibiotics, anti-inflammatory medication, and immunomodulatory therapy.

Both PANS and a subtype condition, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus infections (PANDAS), are underrecognized, Dr. Chang said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists. It is often misdiagnosed as Tourette syndrome or obsessive-compulsive disorder (OCD) because tics are present in about half of cases, he said, but more severe associated symptoms, such as psychosis, can be misdiagnosed as psychotic disorders or mood disorders. Currently, neither PANS nor PANDAS are officially recognized by the American Academy of Pediatrics or the DSM-5.

“We’re hoping that it is soon because it clearly exists,” Dr. Chang said at the meeting, presented by Global Academy for Medical Education. “If you’ve ever treated a child with PANS or PANDAS and you have seen antibiotics totally reverse OCD and tic-like behavior, if you’ve seen prednisone actually treat symptoms of mania or even psychosis and actually make those things better rather than worse, it’s really eye-opening and it makes a believer out of you.”

Anxiety is the most common psychiatric symptom in youth, and anxiety disorders are also common, said Dr. Chang. According to the National Comorbidity Survey: Adolescent Supplement, 2001-2004, 31.9% adolescents overall reported an anxiety disorder, and 8.3% said their anxiety disorder caused severe impairment. The COVID-19 pandemic has increased the level of anxiety for children and adolescents, which can lead to other disorders, such as separation anxiety disorder, panic disorder, specific phobia, social anxiety disorder, acute stress disorder, generalized anxiety disorder, OCD, or posttraumatic stress disorder. Psychiatrists should be suspicious of any sudden onset of symptoms that overlap with PANS, said Dr. Chang, who is now in private practice in Palo Alto, Calif.

“Anxiety disorders are incredibly common. Remember that you’ve got to carefully screen for other anxiety disorders, because they’re highly comorbid,” Dr. Chang said. “You’ve got to do a full workup. If there are other things going on, you’ve got to think PANS. If it’s acute onset, you’ve really got to think [PANS], and you should do that workup or refer to someone who does.”

The prevalence of PANS and PANDAS is not known, but it may be more common than psychiatrists realize, Dr. Chang said. “I’ve been doing this for about 10 years now in the PANS and PANDAS field, and it’s very clear to me that this is something that is prevalent,” he said.

Together with Jennifer Frankovich, MD, Dr. Chang founded a clinic at the Lucile Packard Children’s Hospital Stanford, and also helped to develop treatment guidelines for youth with PANS. At the clinic, patients are approximately 7.7 years old when developing the first symptoms, and are 10.7 years old when presenting for treatment. Most patients at the clinic are male (78%), and 40% are acute onset cases. Nearly all patients have symptoms of anxiety (92%), mood disorder (88%), OCD (86%), sensory/motor abnormalities (88%), irritability/aggression (82%), somatic symptoms, deterioration in school (76%), and behavioral regression (59%). More than one-third present with suicidal ideation (38%) and violence to themselves (29%), others (38%), or objects. About one-fourth have symptoms of psychosis (24%).

“These can be really sick kids,” Dr. Chang said. “We’re talking about kids yelling, screaming, having anxiety attacks, dropping on the floor, doing rituals constantly, not functioning, not able to eat because they’re afraid of things, not able to take care of their body or daily living. These were sometimes highly functional people beforehand, sometimes they weren’t, but it was still an acute change.”
 

Treatment for PANS

Treatment guidelines released by the PANS/PANDAS Consortium in 2017 recommend a first course of antistreptococcal treatment for new PANS cases. Psychiatrists should look for evidence of strep or other infection and use antibiotics to eradicate any underlying acute or residual infection.

“Very commonly, we’ll use things like azithromycin, or Augmentin, or amoxicillin, and you’ll see suddenly the OCD go away or at least diminish, the sleep return to normal, the mood come back down,” Dr. Chang said. “It’s pretty amazing when you see it.”

In other cases, ongoing treatment is needed for longer than the normal 5-day or 10-day course of antibiotics. “We’re not exactly sure how long: sometimes it’s 3 weeks, sometimes it’s 4 weeks, but you have to give it more than a week. Sometimes it’s the anti-inflammatory properties that are helping.” While concerns about haphazardly prescribing antibiotics are valid, “if you can cure this stuff on antibiotics, it’s low-hanging fruit,” Dr. Chang said.

There is evidence in the literature that prescribing antibiotics for PANS is beneficial. A randomized controlled trial published in 2017 showed that patients with PANS prescribed azithromycin for 4 weeks had greater reductions in severity of OCD, compared with placebo.

“We need more studies, but clearly, antibiotics do have the potential to help with certain kids. And certainly, in my practice, I see sometimes a slam-dunk response,” Dr. Chang said. “Unfortunately, sometimes you don’t see a slam-dunk response or you can’t find an infection. That’s when it might be more of an inflammation from some other reason. It could be a leftover infection, or it could be an anti-inflammatory situation.”

Immunomodulatory treatment for PANS includes use of NSAIDs, such as ibuprofen or naproxen sodium; steroids, such as prednisone or intravenous corticosteroids; intravenous immunoglobulin; or plasma exchange. Other therapies to consider are rituximab, mycophenolate mofetil, and cyclophosphamide.

Some psychiatric treatments may help patients with PANS. While there is no empirical evidence that psychotropics are effective in treating PANS, some SSRIs might help if patients are able to handle any adverse events. Psychotherapy and education of the family are also important for patients with PANS and their caregivers.

“Basically, [PANS] has as high a caregiver burden as having someone in the household with Alzheimer’s disease or cancer. It’s a huge burden, it’s very stressful, and the family needs support for this,” Dr. Chang said.

Global Academy and this news organization are owned by the same parent company. Dr. Chang reports he is a consultant for Allergan, Impel NeuroPharma, and Sunovion. He is also on the speaker’s bureau for Sunovion.

Pediatric acute-onset neuropsychiatric syndrome (PANS), a rare acute onset of psychiatric symptoms, might be more common than initially thought, according to Kiki D. Chang, MD.

PANS is characterized by the National Center for Advancing Translational Sciences Genetic and Rare Diseases Information Center as a “sudden onset of obsessive-compulsive symptoms and/or severe eating restrictions, along with at least two other cognitive, behavioral, or neurological symptoms.” These symptoms can include anxiety, depression, oppositional behavior, difficulty concentrating, abnormalities in motor and sensory skills, and other somatic symptoms. The condition develops as a result of an infection that causes an autoimmune or inflammatory response in the brain, and patients tend to respond well to treatment from antibiotics, anti-inflammatory medication, and immunomodulatory therapy.

Both PANS and a subtype condition, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus infections (PANDAS), are underrecognized, Dr. Chang said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists. It is often misdiagnosed as Tourette syndrome or obsessive-compulsive disorder (OCD) because tics are present in about half of cases, he said, but more severe associated symptoms, such as psychosis, can be misdiagnosed as psychotic disorders or mood disorders. Currently, neither PANS nor PANDAS are officially recognized by the American Academy of Pediatrics or the DSM-5.

“We’re hoping that it is soon because it clearly exists,” Dr. Chang said at the meeting, presented by Global Academy for Medical Education. “If you’ve ever treated a child with PANS or PANDAS and you have seen antibiotics totally reverse OCD and tic-like behavior, if you’ve seen prednisone actually treat symptoms of mania or even psychosis and actually make those things better rather than worse, it’s really eye-opening and it makes a believer out of you.”

Anxiety is the most common psychiatric symptom in youth, and anxiety disorders are also common, said Dr. Chang. According to the National Comorbidity Survey: Adolescent Supplement, 2001-2004, 31.9% adolescents overall reported an anxiety disorder, and 8.3% said their anxiety disorder caused severe impairment. The COVID-19 pandemic has increased the level of anxiety for children and adolescents, which can lead to other disorders, such as separation anxiety disorder, panic disorder, specific phobia, social anxiety disorder, acute stress disorder, generalized anxiety disorder, OCD, or posttraumatic stress disorder. Psychiatrists should be suspicious of any sudden onset of symptoms that overlap with PANS, said Dr. Chang, who is now in private practice in Palo Alto, Calif.

“Anxiety disorders are incredibly common. Remember that you’ve got to carefully screen for other anxiety disorders, because they’re highly comorbid,” Dr. Chang said. “You’ve got to do a full workup. If there are other things going on, you’ve got to think PANS. If it’s acute onset, you’ve really got to think [PANS], and you should do that workup or refer to someone who does.”

The prevalence of PANS and PANDAS is not known, but it may be more common than psychiatrists realize, Dr. Chang said. “I’ve been doing this for about 10 years now in the PANS and PANDAS field, and it’s very clear to me that this is something that is prevalent,” he said.

Together with Jennifer Frankovich, MD, Dr. Chang founded a clinic at the Lucile Packard Children’s Hospital Stanford, and also helped to develop treatment guidelines for youth with PANS. At the clinic, patients are approximately 7.7 years old when developing the first symptoms, and are 10.7 years old when presenting for treatment. Most patients at the clinic are male (78%), and 40% are acute onset cases. Nearly all patients have symptoms of anxiety (92%), mood disorder (88%), OCD (86%), sensory/motor abnormalities (88%), irritability/aggression (82%), somatic symptoms, deterioration in school (76%), and behavioral regression (59%). More than one-third present with suicidal ideation (38%) and violence to themselves (29%), others (38%), or objects. About one-fourth have symptoms of psychosis (24%).

“These can be really sick kids,” Dr. Chang said. “We’re talking about kids yelling, screaming, having anxiety attacks, dropping on the floor, doing rituals constantly, not functioning, not able to eat because they’re afraid of things, not able to take care of their body or daily living. These were sometimes highly functional people beforehand, sometimes they weren’t, but it was still an acute change.”
 

Treatment for PANS

Treatment guidelines released by the PANS/PANDAS Consortium in 2017 recommend a first course of antistreptococcal treatment for new PANS cases. Psychiatrists should look for evidence of strep or other infection and use antibiotics to eradicate any underlying acute or residual infection.

“Very commonly, we’ll use things like azithromycin, or Augmentin, or amoxicillin, and you’ll see suddenly the OCD go away or at least diminish, the sleep return to normal, the mood come back down,” Dr. Chang said. “It’s pretty amazing when you see it.”

In other cases, ongoing treatment is needed for longer than the normal 5-day or 10-day course of antibiotics. “We’re not exactly sure how long: sometimes it’s 3 weeks, sometimes it’s 4 weeks, but you have to give it more than a week. Sometimes it’s the anti-inflammatory properties that are helping.” While concerns about haphazardly prescribing antibiotics are valid, “if you can cure this stuff on antibiotics, it’s low-hanging fruit,” Dr. Chang said.

There is evidence in the literature that prescribing antibiotics for PANS is beneficial. A randomized controlled trial published in 2017 showed that patients with PANS prescribed azithromycin for 4 weeks had greater reductions in severity of OCD, compared with placebo.

“We need more studies, but clearly, antibiotics do have the potential to help with certain kids. And certainly, in my practice, I see sometimes a slam-dunk response,” Dr. Chang said. “Unfortunately, sometimes you don’t see a slam-dunk response or you can’t find an infection. That’s when it might be more of an inflammation from some other reason. It could be a leftover infection, or it could be an anti-inflammatory situation.”

Immunomodulatory treatment for PANS includes use of NSAIDs, such as ibuprofen or naproxen sodium; steroids, such as prednisone or intravenous corticosteroids; intravenous immunoglobulin; or plasma exchange. Other therapies to consider are rituximab, mycophenolate mofetil, and cyclophosphamide.

Some psychiatric treatments may help patients with PANS. While there is no empirical evidence that psychotropics are effective in treating PANS, some SSRIs might help if patients are able to handle any adverse events. Psychotherapy and education of the family are also important for patients with PANS and their caregivers.

“Basically, [PANS] has as high a caregiver burden as having someone in the household with Alzheimer’s disease or cancer. It’s a huge burden, it’s very stressful, and the family needs support for this,” Dr. Chang said.

Global Academy and this news organization are owned by the same parent company. Dr. Chang reports he is a consultant for Allergan, Impel NeuroPharma, and Sunovion. He is also on the speaker’s bureau for Sunovion.

Pediatric acute-onset neuropsychiatric syndrome (PANS), a rare acute onset of psychiatric symptoms, might be more common than initially thought, according to Kiki D. Chang, MD.

PANS is characterized by the National Center for Advancing Translational Sciences Genetic and Rare Diseases Information Center as a “sudden onset of obsessive-compulsive symptoms and/or severe eating restrictions, along with at least two other cognitive, behavioral, or neurological symptoms.” These symptoms can include anxiety, depression, oppositional behavior, difficulty concentrating, abnormalities in motor and sensory skills, and other somatic symptoms. The condition develops as a result of an infection that causes an autoimmune or inflammatory response in the brain, and patients tend to respond well to treatment from antibiotics, anti-inflammatory medication, and immunomodulatory therapy.

Both PANS and a subtype condition, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus infections (PANDAS), are underrecognized, Dr. Chang said in a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists. It is often misdiagnosed as Tourette syndrome or obsessive-compulsive disorder (OCD) because tics are present in about half of cases, he said, but more severe associated symptoms, such as psychosis, can be misdiagnosed as psychotic disorders or mood disorders. Currently, neither PANS nor PANDAS are officially recognized by the American Academy of Pediatrics or the DSM-5.

“We’re hoping that it is soon because it clearly exists,” Dr. Chang said at the meeting, presented by Global Academy for Medical Education. “If you’ve ever treated a child with PANS or PANDAS and you have seen antibiotics totally reverse OCD and tic-like behavior, if you’ve seen prednisone actually treat symptoms of mania or even psychosis and actually make those things better rather than worse, it’s really eye-opening and it makes a believer out of you.”

Anxiety is the most common psychiatric symptom in youth, and anxiety disorders are also common, said Dr. Chang. According to the National Comorbidity Survey: Adolescent Supplement, 2001-2004, 31.9% adolescents overall reported an anxiety disorder, and 8.3% said their anxiety disorder caused severe impairment. The COVID-19 pandemic has increased the level of anxiety for children and adolescents, which can lead to other disorders, such as separation anxiety disorder, panic disorder, specific phobia, social anxiety disorder, acute stress disorder, generalized anxiety disorder, OCD, or posttraumatic stress disorder. Psychiatrists should be suspicious of any sudden onset of symptoms that overlap with PANS, said Dr. Chang, who is now in private practice in Palo Alto, Calif.

“Anxiety disorders are incredibly common. Remember that you’ve got to carefully screen for other anxiety disorders, because they’re highly comorbid,” Dr. Chang said. “You’ve got to do a full workup. If there are other things going on, you’ve got to think PANS. If it’s acute onset, you’ve really got to think [PANS], and you should do that workup or refer to someone who does.”

The prevalence of PANS and PANDAS is not known, but it may be more common than psychiatrists realize, Dr. Chang said. “I’ve been doing this for about 10 years now in the PANS and PANDAS field, and it’s very clear to me that this is something that is prevalent,” he said.

Together with Jennifer Frankovich, MD, Dr. Chang founded a clinic at the Lucile Packard Children’s Hospital Stanford, and also helped to develop treatment guidelines for youth with PANS. At the clinic, patients are approximately 7.7 years old when developing the first symptoms, and are 10.7 years old when presenting for treatment. Most patients at the clinic are male (78%), and 40% are acute onset cases. Nearly all patients have symptoms of anxiety (92%), mood disorder (88%), OCD (86%), sensory/motor abnormalities (88%), irritability/aggression (82%), somatic symptoms, deterioration in school (76%), and behavioral regression (59%). More than one-third present with suicidal ideation (38%) and violence to themselves (29%), others (38%), or objects. About one-fourth have symptoms of psychosis (24%).

“These can be really sick kids,” Dr. Chang said. “We’re talking about kids yelling, screaming, having anxiety attacks, dropping on the floor, doing rituals constantly, not functioning, not able to eat because they’re afraid of things, not able to take care of their body or daily living. These were sometimes highly functional people beforehand, sometimes they weren’t, but it was still an acute change.”
 

Treatment for PANS

Treatment guidelines released by the PANS/PANDAS Consortium in 2017 recommend a first course of antistreptococcal treatment for new PANS cases. Psychiatrists should look for evidence of strep or other infection and use antibiotics to eradicate any underlying acute or residual infection.

“Very commonly, we’ll use things like azithromycin, or Augmentin, or amoxicillin, and you’ll see suddenly the OCD go away or at least diminish, the sleep return to normal, the mood come back down,” Dr. Chang said. “It’s pretty amazing when you see it.”

In other cases, ongoing treatment is needed for longer than the normal 5-day or 10-day course of antibiotics. “We’re not exactly sure how long: sometimes it’s 3 weeks, sometimes it’s 4 weeks, but you have to give it more than a week. Sometimes it’s the anti-inflammatory properties that are helping.” While concerns about haphazardly prescribing antibiotics are valid, “if you can cure this stuff on antibiotics, it’s low-hanging fruit,” Dr. Chang said.

There is evidence in the literature that prescribing antibiotics for PANS is beneficial. A randomized controlled trial published in 2017 showed that patients with PANS prescribed azithromycin for 4 weeks had greater reductions in severity of OCD, compared with placebo.

“We need more studies, but clearly, antibiotics do have the potential to help with certain kids. And certainly, in my practice, I see sometimes a slam-dunk response,” Dr. Chang said. “Unfortunately, sometimes you don’t see a slam-dunk response or you can’t find an infection. That’s when it might be more of an inflammation from some other reason. It could be a leftover infection, or it could be an anti-inflammatory situation.”

Immunomodulatory treatment for PANS includes use of NSAIDs, such as ibuprofen or naproxen sodium; steroids, such as prednisone or intravenous corticosteroids; intravenous immunoglobulin; or plasma exchange. Other therapies to consider are rituximab, mycophenolate mofetil, and cyclophosphamide.

Some psychiatric treatments may help patients with PANS. While there is no empirical evidence that psychotropics are effective in treating PANS, some SSRIs might help if patients are able to handle any adverse events. Psychotherapy and education of the family are also important for patients with PANS and their caregivers.

“Basically, [PANS] has as high a caregiver burden as having someone in the household with Alzheimer’s disease or cancer. It’s a huge burden, it’s very stressful, and the family needs support for this,” Dr. Chang said.

Global Academy and this news organization are owned by the same parent company. Dr. Chang reports he is a consultant for Allergan, Impel NeuroPharma, and Sunovion. He is also on the speaker’s bureau for Sunovion.

Middle-aged individuals who have sleep apnea or who get 9 or more hours of sleep at night have more than double the risk of developing Alzheimer’s disease within about 6 years, new research suggests. A U.K. Biobank study of more than 500,000 individuals also showed that excessive daytime sleepiness was associated with increased risk for Alzheimer’s disease.

“Addressing sleep problems in middle-age may play a role in improving brain health,” said lead author Lei Gao, MD, assistant professor of anesthesia at Harvard Medical School and associate scientist in the division of sleep and circadian disorders at Brigham and Women’s Hospital, both in Boston.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference 2020.
 

Intricately linked

Sleep disturbances are common and on the rise around the world. In recent years, researchers have become increasingly aware of the intricate link between sleep health and brain health, Dr. Gao noted.

The current study included 502,538 individuals from the U.K. Biobank (mean age, 57 years) who were free from Alzheimer’s disease at baseline. They were followed for up to 12 years. The participants self-reported sleep traits, including hours of nighttime sleep, daytime sleepiness, sleep apnea diagnosis, snoring, and napping. Researchers determined Alzheimer’s disease diagnoses from hospital admissions and from death registries.

In addition to adjusting for age, sex, education, and ethnicity, the full model adjusted for socioeconomic status, body mass index, physical activity, smoking and alcohol use, cardiovascular diseases and risk factors, neurological diseases, respiratory diseases, depression/anxiety, and medication use. Over the course of a mean follow-up of 6.4 years, 932 participants developed Alzheimer’s disease.
 

Complex disorder

Compared with those who got an average of 6-9 hours of sleep per night, those getting more than 9 hours had a higher risk for Alzheimer’s disease (hazard ratio, 2.04; 95% confidence interval, 1.56-2.67; P < .001). Having sleep apnea also raised the risk significantly (HR, 2.05; 95% CI, 1.23-3.42; P = .006), as did daytime sleepiness (HR, 1.56; 95% CI, 1.18-2.03; P = .001).

Dr. Gao noted that daytime sleepiness and sleep apnea remained predictive after controlling for sleep duration. “In fact, all three sleep traits remained associated with Alzheimer’s disease within the same model, suggesting some degree of independence.”

Interestingly, snoring, which is a common symptom of sleep apnea, was not linked to Alzheimer’s disease risk. The “vast majority” of people who snore don’t meet criteria for a diagnosis of sleep apnea, which was particularly true for this large cohort of relatively healthy study participants, Dr. Gao noted.

“Sleep apnea is a complex, multisystemic sleep disorder associated with obesity, high blood pressure, and often other heart problems,” he said.

He added that, as an anesthesiologist, he is particularly wary if patients have this condition, “given their increased risk for airway difficulties, adverse cardiac events, postoperative respiratory complications, and confusion or delirium, which is also associated with higher risk for eventual Alzheimer’s disease and death.”

These multisystemic factors may be driving the link to Alzheimer’s disease. “We certainly need to address this better as the population ages and obesity rates rise,” Dr. Gao said.
 

No association with napping

Unlike another of Dr. Gao’s studies that was conducted in a much older population, napping was not a risk factor for Alzheimer’s disease in the current study’s younger participants. It could be that the impacts of different sleep traits on health outcome change with age, Dr. Gao said, or this could represent a limitation of using self-reported sleep measures as opposed to objective and/or quantitative measures, such as actigraphy. The reasons for napping, which differ around the world with the habit being common in certain parts, may also help explain differences in observed associations.

Although the investigators tried to control for comorbidities and medication use, there “most certainly” could be a reverse causation at work. For example, sleeping too much could be both a cause and a symptom of dementia. Dr. Gao noted that sleep disturbances often become more prevalent with dementia, and sleeping too much or complaining of daytime sleepiness may be a result of preclinical Alzheimer’s disease. Even if there is a reverse causation, however, the average time to Alzheimer’s disease diagnosis was over 6 years in this study. “This may be a significant window of time to intervene,” he said.

To improve sleep health, he recommends going to bed and waking at similar times every day, avoiding caffeine or alcohol close to bedtime, limiting screen time before bed, dimming lights, and reducing noise.

It’s also important to have sleep apnea treated. “While more studies are needed, it’s generally believed that addressing the pauses in breathing, the apnea episodes, will help reduce cardiovascular health risks such as obesity, high blood pressure and heart failure. All are known to be strongly linked to dementia risk,” Dr. Gao said.

Results from an assessment of 100,000 actigraphy records from a subset of the same population are expected soon and will add objective confirmation of these self-reported results, he added.
 

Unique, powerful

Commenting on the findings, Alberto Ramos, MD, associate professor of clinical neurology and research director of the sleep medicine program at the University of Miami, called the study “unique” and “powerful” because of its prospective design and large sample size.

“Another strength of the study was that it included a population-based sample as opposed to one from a memory or sleep clinic where people already have symptoms or are already sick,” said Dr. Ramos, who was not involved with the research.

In addition, while most studies that have linked sleep disturbances with dementia risk have been in older adults, this study’s population was middle-aged to start out, he noted.

Dr. Gao and Dr. Ramos reported no relevant financial relationships. Although Dr. Gao’s lab receives funding from the National Institutes of Health, the BrightFocus Foundation, the University of Manchester, the Medical Biodynamics Program, Brigham and Women’s Hospital, and the Broad Institute, the study itself does not have its own specific funding.

A version of this article originally appeared on Medscape.com.

Middle-aged individuals who have sleep apnea or who get 9 or more hours of sleep at night have more than double the risk of developing Alzheimer’s disease within about 6 years, new research suggests. A U.K. Biobank study of more than 500,000 individuals also showed that excessive daytime sleepiness was associated with increased risk for Alzheimer’s disease.

“Addressing sleep problems in middle-age may play a role in improving brain health,” said lead author Lei Gao, MD, assistant professor of anesthesia at Harvard Medical School and associate scientist in the division of sleep and circadian disorders at Brigham and Women’s Hospital, both in Boston.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference 2020.
 

Intricately linked

Sleep disturbances are common and on the rise around the world. In recent years, researchers have become increasingly aware of the intricate link between sleep health and brain health, Dr. Gao noted.

The current study included 502,538 individuals from the U.K. Biobank (mean age, 57 years) who were free from Alzheimer’s disease at baseline. They were followed for up to 12 years. The participants self-reported sleep traits, including hours of nighttime sleep, daytime sleepiness, sleep apnea diagnosis, snoring, and napping. Researchers determined Alzheimer’s disease diagnoses from hospital admissions and from death registries.

In addition to adjusting for age, sex, education, and ethnicity, the full model adjusted for socioeconomic status, body mass index, physical activity, smoking and alcohol use, cardiovascular diseases and risk factors, neurological diseases, respiratory diseases, depression/anxiety, and medication use. Over the course of a mean follow-up of 6.4 years, 932 participants developed Alzheimer’s disease.
 

Complex disorder

Compared with those who got an average of 6-9 hours of sleep per night, those getting more than 9 hours had a higher risk for Alzheimer’s disease (hazard ratio, 2.04; 95% confidence interval, 1.56-2.67; P < .001). Having sleep apnea also raised the risk significantly (HR, 2.05; 95% CI, 1.23-3.42; P = .006), as did daytime sleepiness (HR, 1.56; 95% CI, 1.18-2.03; P = .001).

Dr. Gao noted that daytime sleepiness and sleep apnea remained predictive after controlling for sleep duration. “In fact, all three sleep traits remained associated with Alzheimer’s disease within the same model, suggesting some degree of independence.”

Interestingly, snoring, which is a common symptom of sleep apnea, was not linked to Alzheimer’s disease risk. The “vast majority” of people who snore don’t meet criteria for a diagnosis of sleep apnea, which was particularly true for this large cohort of relatively healthy study participants, Dr. Gao noted.

“Sleep apnea is a complex, multisystemic sleep disorder associated with obesity, high blood pressure, and often other heart problems,” he said.

He added that, as an anesthesiologist, he is particularly wary if patients have this condition, “given their increased risk for airway difficulties, adverse cardiac events, postoperative respiratory complications, and confusion or delirium, which is also associated with higher risk for eventual Alzheimer’s disease and death.”

These multisystemic factors may be driving the link to Alzheimer’s disease. “We certainly need to address this better as the population ages and obesity rates rise,” Dr. Gao said.
 

No association with napping

Unlike another of Dr. Gao’s studies that was conducted in a much older population, napping was not a risk factor for Alzheimer’s disease in the current study’s younger participants. It could be that the impacts of different sleep traits on health outcome change with age, Dr. Gao said, or this could represent a limitation of using self-reported sleep measures as opposed to objective and/or quantitative measures, such as actigraphy. The reasons for napping, which differ around the world with the habit being common in certain parts, may also help explain differences in observed associations.

Although the investigators tried to control for comorbidities and medication use, there “most certainly” could be a reverse causation at work. For example, sleeping too much could be both a cause and a symptom of dementia. Dr. Gao noted that sleep disturbances often become more prevalent with dementia, and sleeping too much or complaining of daytime sleepiness may be a result of preclinical Alzheimer’s disease. Even if there is a reverse causation, however, the average time to Alzheimer’s disease diagnosis was over 6 years in this study. “This may be a significant window of time to intervene,” he said.

To improve sleep health, he recommends going to bed and waking at similar times every day, avoiding caffeine or alcohol close to bedtime, limiting screen time before bed, dimming lights, and reducing noise.

It’s also important to have sleep apnea treated. “While more studies are needed, it’s generally believed that addressing the pauses in breathing, the apnea episodes, will help reduce cardiovascular health risks such as obesity, high blood pressure and heart failure. All are known to be strongly linked to dementia risk,” Dr. Gao said.

Results from an assessment of 100,000 actigraphy records from a subset of the same population are expected soon and will add objective confirmation of these self-reported results, he added.
 

Unique, powerful

Commenting on the findings, Alberto Ramos, MD, associate professor of clinical neurology and research director of the sleep medicine program at the University of Miami, called the study “unique” and “powerful” because of its prospective design and large sample size.

“Another strength of the study was that it included a population-based sample as opposed to one from a memory or sleep clinic where people already have symptoms or are already sick,” said Dr. Ramos, who was not involved with the research.

In addition, while most studies that have linked sleep disturbances with dementia risk have been in older adults, this study’s population was middle-aged to start out, he noted.

Dr. Gao and Dr. Ramos reported no relevant financial relationships. Although Dr. Gao’s lab receives funding from the National Institutes of Health, the BrightFocus Foundation, the University of Manchester, the Medical Biodynamics Program, Brigham and Women’s Hospital, and the Broad Institute, the study itself does not have its own specific funding.

A version of this article originally appeared on Medscape.com.

Middle-aged individuals who have sleep apnea or who get 9 or more hours of sleep at night have more than double the risk of developing Alzheimer’s disease within about 6 years, new research suggests. A U.K. Biobank study of more than 500,000 individuals also showed that excessive daytime sleepiness was associated with increased risk for Alzheimer’s disease.

“Addressing sleep problems in middle-age may play a role in improving brain health,” said lead author Lei Gao, MD, assistant professor of anesthesia at Harvard Medical School and associate scientist in the division of sleep and circadian disorders at Brigham and Women’s Hospital, both in Boston.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference 2020.
 

Intricately linked

Sleep disturbances are common and on the rise around the world. In recent years, researchers have become increasingly aware of the intricate link between sleep health and brain health, Dr. Gao noted.

The current study included 502,538 individuals from the U.K. Biobank (mean age, 57 years) who were free from Alzheimer’s disease at baseline. They were followed for up to 12 years. The participants self-reported sleep traits, including hours of nighttime sleep, daytime sleepiness, sleep apnea diagnosis, snoring, and napping. Researchers determined Alzheimer’s disease diagnoses from hospital admissions and from death registries.

In addition to adjusting for age, sex, education, and ethnicity, the full model adjusted for socioeconomic status, body mass index, physical activity, smoking and alcohol use, cardiovascular diseases and risk factors, neurological diseases, respiratory diseases, depression/anxiety, and medication use. Over the course of a mean follow-up of 6.4 years, 932 participants developed Alzheimer’s disease.
 

Complex disorder

Compared with those who got an average of 6-9 hours of sleep per night, those getting more than 9 hours had a higher risk for Alzheimer’s disease (hazard ratio, 2.04; 95% confidence interval, 1.56-2.67; P < .001). Having sleep apnea also raised the risk significantly (HR, 2.05; 95% CI, 1.23-3.42; P = .006), as did daytime sleepiness (HR, 1.56; 95% CI, 1.18-2.03; P = .001).

Dr. Gao noted that daytime sleepiness and sleep apnea remained predictive after controlling for sleep duration. “In fact, all three sleep traits remained associated with Alzheimer’s disease within the same model, suggesting some degree of independence.”

Interestingly, snoring, which is a common symptom of sleep apnea, was not linked to Alzheimer’s disease risk. The “vast majority” of people who snore don’t meet criteria for a diagnosis of sleep apnea, which was particularly true for this large cohort of relatively healthy study participants, Dr. Gao noted.

“Sleep apnea is a complex, multisystemic sleep disorder associated with obesity, high blood pressure, and often other heart problems,” he said.

He added that, as an anesthesiologist, he is particularly wary if patients have this condition, “given their increased risk for airway difficulties, adverse cardiac events, postoperative respiratory complications, and confusion or delirium, which is also associated with higher risk for eventual Alzheimer’s disease and death.”

These multisystemic factors may be driving the link to Alzheimer’s disease. “We certainly need to address this better as the population ages and obesity rates rise,” Dr. Gao said.
 

No association with napping

Unlike another of Dr. Gao’s studies that was conducted in a much older population, napping was not a risk factor for Alzheimer’s disease in the current study’s younger participants. It could be that the impacts of different sleep traits on health outcome change with age, Dr. Gao said, or this could represent a limitation of using self-reported sleep measures as opposed to objective and/or quantitative measures, such as actigraphy. The reasons for napping, which differ around the world with the habit being common in certain parts, may also help explain differences in observed associations.

Although the investigators tried to control for comorbidities and medication use, there “most certainly” could be a reverse causation at work. For example, sleeping too much could be both a cause and a symptom of dementia. Dr. Gao noted that sleep disturbances often become more prevalent with dementia, and sleeping too much or complaining of daytime sleepiness may be a result of preclinical Alzheimer’s disease. Even if there is a reverse causation, however, the average time to Alzheimer’s disease diagnosis was over 6 years in this study. “This may be a significant window of time to intervene,” he said.

To improve sleep health, he recommends going to bed and waking at similar times every day, avoiding caffeine or alcohol close to bedtime, limiting screen time before bed, dimming lights, and reducing noise.

It’s also important to have sleep apnea treated. “While more studies are needed, it’s generally believed that addressing the pauses in breathing, the apnea episodes, will help reduce cardiovascular health risks such as obesity, high blood pressure and heart failure. All are known to be strongly linked to dementia risk,” Dr. Gao said.

Results from an assessment of 100,000 actigraphy records from a subset of the same population are expected soon and will add objective confirmation of these self-reported results, he added.
 

Unique, powerful

Commenting on the findings, Alberto Ramos, MD, associate professor of clinical neurology and research director of the sleep medicine program at the University of Miami, called the study “unique” and “powerful” because of its prospective design and large sample size.

“Another strength of the study was that it included a population-based sample as opposed to one from a memory or sleep clinic where people already have symptoms or are already sick,” said Dr. Ramos, who was not involved with the research.

In addition, while most studies that have linked sleep disturbances with dementia risk have been in older adults, this study’s population was middle-aged to start out, he noted.

Dr. Gao and Dr. Ramos reported no relevant financial relationships. Although Dr. Gao’s lab receives funding from the National Institutes of Health, the BrightFocus Foundation, the University of Manchester, the Medical Biodynamics Program, Brigham and Women’s Hospital, and the Broad Institute, the study itself does not have its own specific funding.

A version of this article originally appeared on Medscape.com.

Infection increases mortality risk among patients with dementia, new research suggests. A large, registry-based cohort study showed that those with dementia had a greater than sixfold increased risk of dying after acquiring any infection than those without dementia or an infection.

“This is the first study to our knowledge to show that increased mortality is observed across all infection types in people with dementia and that increased mortality is seen both short and long term,” said coinvestigator Janet Janbek, a PhD student at the Danish Dementia Research Center, Rigshospitalet, University of Copenhagen.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.

Large Danish cohort

The investigators analyzed data from Danish national health registries for nearly 1.5 million individuals aged 65 years and older who had visited the hospital with an infection. There were 575,260 deaths during more than 12.7 million person-years of follow-up.

Patients with dementia who also had a hospital visit for infection died at a 6.5 times higher rate than participants without dementia or an infection. Those with either dementia alone or infection-related contacts alone had a threefold increased rate of death.

The mortality rate was highest within the first 30 days following the hospital visit for infection. However, the rate remained elevated for 10 years after the initial infection-related hospital visit.

Mortality rates from all infections, including major infections, such as sepsis, down to minor ear infections were elevated in patients with dementia, compared with people who did not have dementia or an infection-related hospital visit.

Ms. Janbek said there are several possible explanations for the association of infection and increased mortality risk in those with dementia. “After a hospital contact with a severe infection, people with dementia may become more reliant on external care, become more frail, and have declined functional levels, which might explain the observed association.”

It might also be that patients with dementia have more severe infections than those without dementia at the time of hospital contact, possibly because of delayed diagnosis, which could explain the higher mortality rates, said Ms. Janbek.

“It is also plausible that infections play a role in worsening dementia and subsequently lead to increased mortality,” she noted.

“Clinicians and health care personnel need to pay closer attention to infections of all types in people with dementia, and steps toward better clinical management and improved posthospital care need to be explored and undertaken. We need to identify possible preventive measures and targeted interventions in people with dementia and infections,” Ms. Janbek said.
 

‘Interesting observation’

Commenting on the study, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said it presents “an interesting observation.” However, “we can’t make any direct assumptions from this research per se about infections and dementia and whether they are causative in any way,” noted Dr. Edelmayer, who was not involved with the study.

Instead, the study highlighted the importance of “taking care of our overall health and making sure that individuals that might be vulnerable to infection, like those who are already living with dementia, are getting the best care possible,” she said.

Ms. Janbek and Dr. Edelmayer have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Infection increases mortality risk among patients with dementia, new research suggests. A large, registry-based cohort study showed that those with dementia had a greater than sixfold increased risk of dying after acquiring any infection than those without dementia or an infection.

“This is the first study to our knowledge to show that increased mortality is observed across all infection types in people with dementia and that increased mortality is seen both short and long term,” said coinvestigator Janet Janbek, a PhD student at the Danish Dementia Research Center, Rigshospitalet, University of Copenhagen.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.

Large Danish cohort

The investigators analyzed data from Danish national health registries for nearly 1.5 million individuals aged 65 years and older who had visited the hospital with an infection. There were 575,260 deaths during more than 12.7 million person-years of follow-up.

Patients with dementia who also had a hospital visit for infection died at a 6.5 times higher rate than participants without dementia or an infection. Those with either dementia alone or infection-related contacts alone had a threefold increased rate of death.

The mortality rate was highest within the first 30 days following the hospital visit for infection. However, the rate remained elevated for 10 years after the initial infection-related hospital visit.

Mortality rates from all infections, including major infections, such as sepsis, down to minor ear infections were elevated in patients with dementia, compared with people who did not have dementia or an infection-related hospital visit.

Ms. Janbek said there are several possible explanations for the association of infection and increased mortality risk in those with dementia. “After a hospital contact with a severe infection, people with dementia may become more reliant on external care, become more frail, and have declined functional levels, which might explain the observed association.”

It might also be that patients with dementia have more severe infections than those without dementia at the time of hospital contact, possibly because of delayed diagnosis, which could explain the higher mortality rates, said Ms. Janbek.

“It is also plausible that infections play a role in worsening dementia and subsequently lead to increased mortality,” she noted.

“Clinicians and health care personnel need to pay closer attention to infections of all types in people with dementia, and steps toward better clinical management and improved posthospital care need to be explored and undertaken. We need to identify possible preventive measures and targeted interventions in people with dementia and infections,” Ms. Janbek said.
 

‘Interesting observation’

Commenting on the study, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said it presents “an interesting observation.” However, “we can’t make any direct assumptions from this research per se about infections and dementia and whether they are causative in any way,” noted Dr. Edelmayer, who was not involved with the study.

Instead, the study highlighted the importance of “taking care of our overall health and making sure that individuals that might be vulnerable to infection, like those who are already living with dementia, are getting the best care possible,” she said.

Ms. Janbek and Dr. Edelmayer have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Infection increases mortality risk among patients with dementia, new research suggests. A large, registry-based cohort study showed that those with dementia had a greater than sixfold increased risk of dying after acquiring any infection than those without dementia or an infection.

“This is the first study to our knowledge to show that increased mortality is observed across all infection types in people with dementia and that increased mortality is seen both short and long term,” said coinvestigator Janet Janbek, a PhD student at the Danish Dementia Research Center, Rigshospitalet, University of Copenhagen.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.

Large Danish cohort

The investigators analyzed data from Danish national health registries for nearly 1.5 million individuals aged 65 years and older who had visited the hospital with an infection. There were 575,260 deaths during more than 12.7 million person-years of follow-up.

Patients with dementia who also had a hospital visit for infection died at a 6.5 times higher rate than participants without dementia or an infection. Those with either dementia alone or infection-related contacts alone had a threefold increased rate of death.

The mortality rate was highest within the first 30 days following the hospital visit for infection. However, the rate remained elevated for 10 years after the initial infection-related hospital visit.

Mortality rates from all infections, including major infections, such as sepsis, down to minor ear infections were elevated in patients with dementia, compared with people who did not have dementia or an infection-related hospital visit.

Ms. Janbek said there are several possible explanations for the association of infection and increased mortality risk in those with dementia. “After a hospital contact with a severe infection, people with dementia may become more reliant on external care, become more frail, and have declined functional levels, which might explain the observed association.”

It might also be that patients with dementia have more severe infections than those without dementia at the time of hospital contact, possibly because of delayed diagnosis, which could explain the higher mortality rates, said Ms. Janbek.

“It is also plausible that infections play a role in worsening dementia and subsequently lead to increased mortality,” she noted.

“Clinicians and health care personnel need to pay closer attention to infections of all types in people with dementia, and steps toward better clinical management and improved posthospital care need to be explored and undertaken. We need to identify possible preventive measures and targeted interventions in people with dementia and infections,” Ms. Janbek said.
 

‘Interesting observation’

Commenting on the study, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said it presents “an interesting observation.” However, “we can’t make any direct assumptions from this research per se about infections and dementia and whether they are causative in any way,” noted Dr. Edelmayer, who was not involved with the study.

Instead, the study highlighted the importance of “taking care of our overall health and making sure that individuals that might be vulnerable to infection, like those who are already living with dementia, are getting the best care possible,” she said.

Ms. Janbek and Dr. Edelmayer have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Two new long-term studies, one an extension trial and the other an analysis of real-world experience, show that the RNS System direct brain responsive neurostimulator leads to reduction of seizure frequency in most epilepsy patients who had it implanted. Both studies showed that the benefit from the devices increased over time.

That accruing benefit may be because of improved protocols as clinicians gain experience with the device or because of network remodeling that occurs over time as seizures are controlled. “I think it’s both,” said Martha Morrell, MD, a clinical professor of neurology at Stanford (Calif.) University and chief medical officer at NeuroPace, the company that has marketed the device since it gained FDA approval in 2013.

In both studies, the slope of improvement over time was similar, but the real-world study showed greater improvement at the beginning of treatment. “I think the slopes represent physiological changes, but the fact that [the real-world study] starts with better outcomes is, I think, directly attributable to learning. When the long-term study was started in 2004, this had never been done before, and we had to make a highly educated guess about what we should do, and the initial stimulatory parameters were programmed in a way that’s very similar to what was used for movement disorders,” Dr. Morrell said in an interview.

The long-term treatment study appeared online July 20 in the journal Neurology, while the real-world analysis was published July 13 in Epilepsia.
 

An alternative option

Medications can effectively treat some seizures, but 30%-40% of patients must turn to other options for control. Surgery can sometimes be curative, but is not suitable for some patients. Other stimulation devices include vagus nerve stimulation (VNS), which sends pulses from a chest implant to the vagus nerve, reducing epileptic attacks through an unknown mechanism. Deep brain stimulation (DBS) places electrodes that deliver stimulation to the anterior nucleus of the thalamus, which can spread initially localized seizures.

The RNS device consists of a neurostimulator implanted cranially and connected to leads that are placed based on the individual patient’s seizure focus or foci. It also continuously monitors brain activity and delivers stimulation only when its signal suggests the beginning of a seizure.

That capacity for recording is a key benefit because the information can be stored and analyzed, according to Vikram Rao, MD, PhD, a coinvestigator in the real-world trial and an associate professor and the epilepsy division chief at the University of California, San Francisco, which was one of the trial centers. “You know more precisely than we previously did how many seizures a patient is having. Many of our patients are not able to quantify their seizures with perfect accuracy, so we’re better quantifying their seizure burden,” Dr. Rao said in an interview.

The ability to monitor patients can also improve clinical management. Dr. Morrell recounted an elderly patient who for many years has driven 5 hours for appointments. Recently she was able to review his data from the RNS System remotely. She determined that he was doing fine and, after a telephone consultation, told him he didn’t need to come in for a scheduled visit.
 

Real-world analysis

In the real-world analysis, researchers led by Babak Razavi, PhD, and Casey Halpern, MD, at Stanford University conducted a chart review of 150 patients at eight centers who underwent treatment with the RNS system between 2013 and 2018. All patients were followed at least 1 year, with a mean of 2.3 years. Patients had a median of 7.7 disabling seizures per month. The mean value was 52 and the numbers ranged from 0.1 to 3,000. A total of 60% had abnormal brain MRI findings.

At 1 year, subjects achieved a mean 67% decrease in seizure frequency (interquartile range, 50%-94%). At 2 years, that grew to 77%; at 3 or more years, 84%. There was no significant difference in seizure reduction at 1 year according to age, age at epilepsy onset, duration of epilepsy, location of seizure foci, presence of brain MRI abnormalities, prior intracranial monitoring, prior epilepsy surgery, or prior VNS treatment. When patients who underwent a resection at the time of RNS placement were excluded, the results were similar. There were no significant differences in outcome by center.

A total of 11.3% of patients experienced a device-related serious adverse event, and 4% developed infections. The rate of infection was not significantly different between patients who had the neurostimulator and leads implanted alone (3.0%) and patients who had intracranial EEG diagnostic monitoring (ICM) electrodes removed at the same time (6.1%; P = .38).

Although about one-third of the patients who started the long-term study dropped out before completion, most were because the participants moved away from treatment centers, according to Dr. Morrell, and other evidence points squarely to patient satisfaction. “At the end of the battery’s longevity, the neurostimulator needs to be replaced. It’s an outpatient, 45-minute procedure. Over 90% of patients chose to have it replaced. It’s not the answer for everybody, but the substantial majority of patients choose to continue,” she said.
 

Extension trial

The open-label extension trial, led by Dileep Nair, MD, of the Cleveland Clinic Foundation and Dr. Morrell, followed 230 of the 256 patients who participated in 2-year phase 3 study or feasibility studies, extending device usage to 9 years. A total of 162 completed follow-up (mean, 7.5 years). The median reduction of seizure frequency was 58% at the end of year 3, and 75% by year 9 (P < .0001; Wilcoxon signed rank). Although patient population enrichment could have explained this observation, other analyses confirmed that the improvement was real.

Nearly 75% had at least a 50% reduction in seizure frequency; 35% had a 90% or greater reduction in seizure frequency. Some patients (18.4%) had at least a full year with no seizures, and 62% who had a 1-year seizure-free period experienced no seizures at the latest follow-up. Overall, 21% had no seizures in the last 6 months of follow-up.

For those with a seizure-free period of more than 1 year, the average duration was 3.2 years (range, 1.04-9.6 years). There was no difference in response among patients based on previous antiseizure medication use or previous epilepsy surgery, VNS treatment, or intracranial monitoring, and there were no differences by patient age at enrollment, age of seizure onset, brain imaging abnormality, seizure onset locality, or number of foci.

The researchers noted improvement in overall Quality of Life in Epilepsy Inventory–89 scores at 1 year (mean, +3.2; P < .0001), which continued through year 9 (mean, +1.9; P < .05). Improvements were also seen in epilepsy targeted (mean, +4.5; P < .001) and cognitive domains (mean, +2.5; P = .005). Risk of infection was 4.1% per procedure, and 12.1% of subjects overall experienced a serious device-related implant infection. Of 35 infections, 16 led to device removal.

The extension study was funded by NeuroPace. NeuroPace supported data entry and institutional review board submission for the real-world trial. Dr. Morrell owns stock and is an employee of NeuroPace. Dr Rao has received support from and/or consulted for NeuroPace.

SOURCE: Nair DR et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010154. Razavi B et al. Epilepsia. 2020 Jul 13. doi: 10.1111/epi.16593.

Two new long-term studies, one an extension trial and the other an analysis of real-world experience, show that the RNS System direct brain responsive neurostimulator leads to reduction of seizure frequency in most epilepsy patients who had it implanted. Both studies showed that the benefit from the devices increased over time.

That accruing benefit may be because of improved protocols as clinicians gain experience with the device or because of network remodeling that occurs over time as seizures are controlled. “I think it’s both,” said Martha Morrell, MD, a clinical professor of neurology at Stanford (Calif.) University and chief medical officer at NeuroPace, the company that has marketed the device since it gained FDA approval in 2013.

In both studies, the slope of improvement over time was similar, but the real-world study showed greater improvement at the beginning of treatment. “I think the slopes represent physiological changes, but the fact that [the real-world study] starts with better outcomes is, I think, directly attributable to learning. When the long-term study was started in 2004, this had never been done before, and we had to make a highly educated guess about what we should do, and the initial stimulatory parameters were programmed in a way that’s very similar to what was used for movement disorders,” Dr. Morrell said in an interview.

The long-term treatment study appeared online July 20 in the journal Neurology, while the real-world analysis was published July 13 in Epilepsia.
 

An alternative option

Medications can effectively treat some seizures, but 30%-40% of patients must turn to other options for control. Surgery can sometimes be curative, but is not suitable for some patients. Other stimulation devices include vagus nerve stimulation (VNS), which sends pulses from a chest implant to the vagus nerve, reducing epileptic attacks through an unknown mechanism. Deep brain stimulation (DBS) places electrodes that deliver stimulation to the anterior nucleus of the thalamus, which can spread initially localized seizures.

The RNS device consists of a neurostimulator implanted cranially and connected to leads that are placed based on the individual patient’s seizure focus or foci. It also continuously monitors brain activity and delivers stimulation only when its signal suggests the beginning of a seizure.

That capacity for recording is a key benefit because the information can be stored and analyzed, according to Vikram Rao, MD, PhD, a coinvestigator in the real-world trial and an associate professor and the epilepsy division chief at the University of California, San Francisco, which was one of the trial centers. “You know more precisely than we previously did how many seizures a patient is having. Many of our patients are not able to quantify their seizures with perfect accuracy, so we’re better quantifying their seizure burden,” Dr. Rao said in an interview.

The ability to monitor patients can also improve clinical management. Dr. Morrell recounted an elderly patient who for many years has driven 5 hours for appointments. Recently she was able to review his data from the RNS System remotely. She determined that he was doing fine and, after a telephone consultation, told him he didn’t need to come in for a scheduled visit.
 

Real-world analysis

In the real-world analysis, researchers led by Babak Razavi, PhD, and Casey Halpern, MD, at Stanford University conducted a chart review of 150 patients at eight centers who underwent treatment with the RNS system between 2013 and 2018. All patients were followed at least 1 year, with a mean of 2.3 years. Patients had a median of 7.7 disabling seizures per month. The mean value was 52 and the numbers ranged from 0.1 to 3,000. A total of 60% had abnormal brain MRI findings.

At 1 year, subjects achieved a mean 67% decrease in seizure frequency (interquartile range, 50%-94%). At 2 years, that grew to 77%; at 3 or more years, 84%. There was no significant difference in seizure reduction at 1 year according to age, age at epilepsy onset, duration of epilepsy, location of seizure foci, presence of brain MRI abnormalities, prior intracranial monitoring, prior epilepsy surgery, or prior VNS treatment. When patients who underwent a resection at the time of RNS placement were excluded, the results were similar. There were no significant differences in outcome by center.

A total of 11.3% of patients experienced a device-related serious adverse event, and 4% developed infections. The rate of infection was not significantly different between patients who had the neurostimulator and leads implanted alone (3.0%) and patients who had intracranial EEG diagnostic monitoring (ICM) electrodes removed at the same time (6.1%; P = .38).

Although about one-third of the patients who started the long-term study dropped out before completion, most were because the participants moved away from treatment centers, according to Dr. Morrell, and other evidence points squarely to patient satisfaction. “At the end of the battery’s longevity, the neurostimulator needs to be replaced. It’s an outpatient, 45-minute procedure. Over 90% of patients chose to have it replaced. It’s not the answer for everybody, but the substantial majority of patients choose to continue,” she said.
 

Extension trial

The open-label extension trial, led by Dileep Nair, MD, of the Cleveland Clinic Foundation and Dr. Morrell, followed 230 of the 256 patients who participated in 2-year phase 3 study or feasibility studies, extending device usage to 9 years. A total of 162 completed follow-up (mean, 7.5 years). The median reduction of seizure frequency was 58% at the end of year 3, and 75% by year 9 (P < .0001; Wilcoxon signed rank). Although patient population enrichment could have explained this observation, other analyses confirmed that the improvement was real.

Nearly 75% had at least a 50% reduction in seizure frequency; 35% had a 90% or greater reduction in seizure frequency. Some patients (18.4%) had at least a full year with no seizures, and 62% who had a 1-year seizure-free period experienced no seizures at the latest follow-up. Overall, 21% had no seizures in the last 6 months of follow-up.

For those with a seizure-free period of more than 1 year, the average duration was 3.2 years (range, 1.04-9.6 years). There was no difference in response among patients based on previous antiseizure medication use or previous epilepsy surgery, VNS treatment, or intracranial monitoring, and there were no differences by patient age at enrollment, age of seizure onset, brain imaging abnormality, seizure onset locality, or number of foci.

The researchers noted improvement in overall Quality of Life in Epilepsy Inventory–89 scores at 1 year (mean, +3.2; P < .0001), which continued through year 9 (mean, +1.9; P < .05). Improvements were also seen in epilepsy targeted (mean, +4.5; P < .001) and cognitive domains (mean, +2.5; P = .005). Risk of infection was 4.1% per procedure, and 12.1% of subjects overall experienced a serious device-related implant infection. Of 35 infections, 16 led to device removal.

The extension study was funded by NeuroPace. NeuroPace supported data entry and institutional review board submission for the real-world trial. Dr. Morrell owns stock and is an employee of NeuroPace. Dr Rao has received support from and/or consulted for NeuroPace.

SOURCE: Nair DR et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010154. Razavi B et al. Epilepsia. 2020 Jul 13. doi: 10.1111/epi.16593.

Two new long-term studies, one an extension trial and the other an analysis of real-world experience, show that the RNS System direct brain responsive neurostimulator leads to reduction of seizure frequency in most epilepsy patients who had it implanted. Both studies showed that the benefit from the devices increased over time.

That accruing benefit may be because of improved protocols as clinicians gain experience with the device or because of network remodeling that occurs over time as seizures are controlled. “I think it’s both,” said Martha Morrell, MD, a clinical professor of neurology at Stanford (Calif.) University and chief medical officer at NeuroPace, the company that has marketed the device since it gained FDA approval in 2013.

In both studies, the slope of improvement over time was similar, but the real-world study showed greater improvement at the beginning of treatment. “I think the slopes represent physiological changes, but the fact that [the real-world study] starts with better outcomes is, I think, directly attributable to learning. When the long-term study was started in 2004, this had never been done before, and we had to make a highly educated guess about what we should do, and the initial stimulatory parameters were programmed in a way that’s very similar to what was used for movement disorders,” Dr. Morrell said in an interview.

The long-term treatment study appeared online July 20 in the journal Neurology, while the real-world analysis was published July 13 in Epilepsia.
 

An alternative option

Medications can effectively treat some seizures, but 30%-40% of patients must turn to other options for control. Surgery can sometimes be curative, but is not suitable for some patients. Other stimulation devices include vagus nerve stimulation (VNS), which sends pulses from a chest implant to the vagus nerve, reducing epileptic attacks through an unknown mechanism. Deep brain stimulation (DBS) places electrodes that deliver stimulation to the anterior nucleus of the thalamus, which can spread initially localized seizures.

The RNS device consists of a neurostimulator implanted cranially and connected to leads that are placed based on the individual patient’s seizure focus or foci. It also continuously monitors brain activity and delivers stimulation only when its signal suggests the beginning of a seizure.

That capacity for recording is a key benefit because the information can be stored and analyzed, according to Vikram Rao, MD, PhD, a coinvestigator in the real-world trial and an associate professor and the epilepsy division chief at the University of California, San Francisco, which was one of the trial centers. “You know more precisely than we previously did how many seizures a patient is having. Many of our patients are not able to quantify their seizures with perfect accuracy, so we’re better quantifying their seizure burden,” Dr. Rao said in an interview.

The ability to monitor patients can also improve clinical management. Dr. Morrell recounted an elderly patient who for many years has driven 5 hours for appointments. Recently she was able to review his data from the RNS System remotely. She determined that he was doing fine and, after a telephone consultation, told him he didn’t need to come in for a scheduled visit.
 

Real-world analysis

In the real-world analysis, researchers led by Babak Razavi, PhD, and Casey Halpern, MD, at Stanford University conducted a chart review of 150 patients at eight centers who underwent treatment with the RNS system between 2013 and 2018. All patients were followed at least 1 year, with a mean of 2.3 years. Patients had a median of 7.7 disabling seizures per month. The mean value was 52 and the numbers ranged from 0.1 to 3,000. A total of 60% had abnormal brain MRI findings.

At 1 year, subjects achieved a mean 67% decrease in seizure frequency (interquartile range, 50%-94%). At 2 years, that grew to 77%; at 3 or more years, 84%. There was no significant difference in seizure reduction at 1 year according to age, age at epilepsy onset, duration of epilepsy, location of seizure foci, presence of brain MRI abnormalities, prior intracranial monitoring, prior epilepsy surgery, or prior VNS treatment. When patients who underwent a resection at the time of RNS placement were excluded, the results were similar. There were no significant differences in outcome by center.

A total of 11.3% of patients experienced a device-related serious adverse event, and 4% developed infections. The rate of infection was not significantly different between patients who had the neurostimulator and leads implanted alone (3.0%) and patients who had intracranial EEG diagnostic monitoring (ICM) electrodes removed at the same time (6.1%; P = .38).

Although about one-third of the patients who started the long-term study dropped out before completion, most were because the participants moved away from treatment centers, according to Dr. Morrell, and other evidence points squarely to patient satisfaction. “At the end of the battery’s longevity, the neurostimulator needs to be replaced. It’s an outpatient, 45-minute procedure. Over 90% of patients chose to have it replaced. It’s not the answer for everybody, but the substantial majority of patients choose to continue,” she said.
 

Extension trial

The open-label extension trial, led by Dileep Nair, MD, of the Cleveland Clinic Foundation and Dr. Morrell, followed 230 of the 256 patients who participated in 2-year phase 3 study or feasibility studies, extending device usage to 9 years. A total of 162 completed follow-up (mean, 7.5 years). The median reduction of seizure frequency was 58% at the end of year 3, and 75% by year 9 (P < .0001; Wilcoxon signed rank). Although patient population enrichment could have explained this observation, other analyses confirmed that the improvement was real.

Nearly 75% had at least a 50% reduction in seizure frequency; 35% had a 90% or greater reduction in seizure frequency. Some patients (18.4%) had at least a full year with no seizures, and 62% who had a 1-year seizure-free period experienced no seizures at the latest follow-up. Overall, 21% had no seizures in the last 6 months of follow-up.

For those with a seizure-free period of more than 1 year, the average duration was 3.2 years (range, 1.04-9.6 years). There was no difference in response among patients based on previous antiseizure medication use or previous epilepsy surgery, VNS treatment, or intracranial monitoring, and there were no differences by patient age at enrollment, age of seizure onset, brain imaging abnormality, seizure onset locality, or number of foci.

The researchers noted improvement in overall Quality of Life in Epilepsy Inventory–89 scores at 1 year (mean, +3.2; P < .0001), which continued through year 9 (mean, +1.9; P < .05). Improvements were also seen in epilepsy targeted (mean, +4.5; P < .001) and cognitive domains (mean, +2.5; P = .005). Risk of infection was 4.1% per procedure, and 12.1% of subjects overall experienced a serious device-related implant infection. Of 35 infections, 16 led to device removal.

The extension study was funded by NeuroPace. NeuroPace supported data entry and institutional review board submission for the real-world trial. Dr. Morrell owns stock and is an employee of NeuroPace. Dr Rao has received support from and/or consulted for NeuroPace.

SOURCE: Nair DR et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000010154. Razavi B et al. Epilepsia. 2020 Jul 13. doi: 10.1111/epi.16593.

LEUVEN, Belgium — A 54-year-old woman has suffered the delusion of thinking she is a chicken for 24 hours. This very rare condition, known as zoanthropy, in which people think they are an animal is often not recognised, say researchers from the University of Leuven.

Zoanthropy can include people believing they are, or behaving like, any kind of animal: from a dog, to a lion or tiger, crocodile, snake, or bee.

It’s important to recognise this as a potential symptom of something serious, say the researchers in the July issue of the Belgian Journal of Psychiatry, Tijdschrift voor Psychiatrie.

The delusion can be a sign of an underlying psychiatric disorder, or it can be secondary to structural or functional abnormalities in the brain.

“Additional investigations with brain imaging and electroencephalogram are therefore advised,” say the authors. 
 

Psychiatrists Need to Be Aware That Clinical Zoanthropy Exists

In their paper, they describe the case of the woman who briefly thought she was a chicken, which was followed by her having a generalized epileptic seizure.

“Clinically, we saw a lady who perspired profusely, trembled, blew up her cheeks, and ... seemed to imitate a chicken, [making noises] like clucking, cackling, and crowing like a rooster,” they say.

“After about 10 minutes she seemed to tighten her muscles for a few seconds, her face turned red and for a short time she didn’t react. These symptoms repeated themselves at intervals of a few minutes [and her] consciousness was fluctuating,” with the patient “disoriented in time and space.”

Lead author Dr Athena Beckers of University Psychiatric Centre, KU Leuven, Belgium, said in an interview with MediQuality: “With only 56 case descriptions in the medical literature from 1850 to the present day, the condition is rare. It amounts to about one description every 3 years.

“We suspect, however, that the delusion is not always noticed: the patient shows bizarre behaviour or makes animal sounds, it is probably often catalogued under the general term ‘psychosis’.”

Dr Beckers adds that it is important that the symptoms are recognised, because of the possible underlying causes which can include epilepsy. So this might require a different or complementary treatment “with, for example, antiepileptic drugs”.

“I myself have only seen this type of delusion once, but I ... heard anecdotal stories from other patients whose family member, for example with schizophrenia, sometimes thought he was a cow [during] ... a psychosis.

“After the publication of my article I was also contacted by someone who told me they had experienced the same thing 30 years ago – he thought he was a chicken.

“I think it’s a good thing that we psychiatrists are aware of the fact that clinical zoanthropy exists and may require additional research,” she observed.

Fortunately, this woman’s experience ended well. After about one year of disability, the patient was able to return to work progressively. Her mood remained stable and there were no more psychotic symptoms or any indication of epileptic episodes.
 

Such Delusions Are Rare 

Dr Georges Otte, a recently retired neuropsychiatrist who formerly worked at Ghent University, Belgium, gave his thoughts to Mediquality: “The interface between neurology and psychiatry ... is a fertile meadow on which many crops thrive. But it is in the darkest corners of psychosis that one finds the most bizarre and also rarest excesses.”

There are a number of delusions of identity, said Dr Otte.

These include Cotard’s syndrome, a rare condition marked by the false belief that the person or their body parts are dead, dying, or don’t exist, or Capgras delusion, where the affected person believes that a spouse or close family member has been replaced with an imposter. Delusions can also occur as a result of substance abuse, for example after using psilocybin (magic mushrooms), he added.

“Delusions in which patients are convinced of ‘shape shifting’ (man to animal) are quite rare,” Dr Otte observed.

“In the literature we know that lycanthropy [a person thinks he or she is turning into a werewolf],” has been reported, and has “apparently inspired many authors of horror stories,” he added.

“But it’s not every day that as a psychiatrist, you will encounter such an extreme psychotic depersonalization as someone turning into a chicken.”
 

This article first appeared on Medscape.com.

LEUVEN, Belgium — A 54-year-old woman has suffered the delusion of thinking she is a chicken for 24 hours. This very rare condition, known as zoanthropy, in which people think they are an animal is often not recognised, say researchers from the University of Leuven.

Zoanthropy can include people believing they are, or behaving like, any kind of animal: from a dog, to a lion or tiger, crocodile, snake, or bee.

It’s important to recognise this as a potential symptom of something serious, say the researchers in the July issue of the Belgian Journal of Psychiatry, Tijdschrift voor Psychiatrie.

The delusion can be a sign of an underlying psychiatric disorder, or it can be secondary to structural or functional abnormalities in the brain.

“Additional investigations with brain imaging and electroencephalogram are therefore advised,” say the authors. 
 

Psychiatrists Need to Be Aware That Clinical Zoanthropy Exists

In their paper, they describe the case of the woman who briefly thought she was a chicken, which was followed by her having a generalized epileptic seizure.

“Clinically, we saw a lady who perspired profusely, trembled, blew up her cheeks, and ... seemed to imitate a chicken, [making noises] like clucking, cackling, and crowing like a rooster,” they say.

“After about 10 minutes she seemed to tighten her muscles for a few seconds, her face turned red and for a short time she didn’t react. These symptoms repeated themselves at intervals of a few minutes [and her] consciousness was fluctuating,” with the patient “disoriented in time and space.”

Lead author Dr Athena Beckers of University Psychiatric Centre, KU Leuven, Belgium, said in an interview with MediQuality: “With only 56 case descriptions in the medical literature from 1850 to the present day, the condition is rare. It amounts to about one description every 3 years.

“We suspect, however, that the delusion is not always noticed: the patient shows bizarre behaviour or makes animal sounds, it is probably often catalogued under the general term ‘psychosis’.”

Dr Beckers adds that it is important that the symptoms are recognised, because of the possible underlying causes which can include epilepsy. So this might require a different or complementary treatment “with, for example, antiepileptic drugs”.

“I myself have only seen this type of delusion once, but I ... heard anecdotal stories from other patients whose family member, for example with schizophrenia, sometimes thought he was a cow [during] ... a psychosis.

“After the publication of my article I was also contacted by someone who told me they had experienced the same thing 30 years ago – he thought he was a chicken.

“I think it’s a good thing that we psychiatrists are aware of the fact that clinical zoanthropy exists and may require additional research,” she observed.

Fortunately, this woman’s experience ended well. After about one year of disability, the patient was able to return to work progressively. Her mood remained stable and there were no more psychotic symptoms or any indication of epileptic episodes.
 

Such Delusions Are Rare 

Dr Georges Otte, a recently retired neuropsychiatrist who formerly worked at Ghent University, Belgium, gave his thoughts to Mediquality: “The interface between neurology and psychiatry ... is a fertile meadow on which many crops thrive. But it is in the darkest corners of psychosis that one finds the most bizarre and also rarest excesses.”

There are a number of delusions of identity, said Dr Otte.

These include Cotard’s syndrome, a rare condition marked by the false belief that the person or their body parts are dead, dying, or don’t exist, or Capgras delusion, where the affected person believes that a spouse or close family member has been replaced with an imposter. Delusions can also occur as a result of substance abuse, for example after using psilocybin (magic mushrooms), he added.

“Delusions in which patients are convinced of ‘shape shifting’ (man to animal) are quite rare,” Dr Otte observed.

“In the literature we know that lycanthropy [a person thinks he or she is turning into a werewolf],” has been reported, and has “apparently inspired many authors of horror stories,” he added.

“But it’s not every day that as a psychiatrist, you will encounter such an extreme psychotic depersonalization as someone turning into a chicken.”
 

This article first appeared on Medscape.com.

LEUVEN, Belgium — A 54-year-old woman has suffered the delusion of thinking she is a chicken for 24 hours. This very rare condition, known as zoanthropy, in which people think they are an animal is often not recognised, say researchers from the University of Leuven.

Zoanthropy can include people believing they are, or behaving like, any kind of animal: from a dog, to a lion or tiger, crocodile, snake, or bee.

It’s important to recognise this as a potential symptom of something serious, say the researchers in the July issue of the Belgian Journal of Psychiatry, Tijdschrift voor Psychiatrie.

The delusion can be a sign of an underlying psychiatric disorder, or it can be secondary to structural or functional abnormalities in the brain.

“Additional investigations with brain imaging and electroencephalogram are therefore advised,” say the authors. 
 

Psychiatrists Need to Be Aware That Clinical Zoanthropy Exists

In their paper, they describe the case of the woman who briefly thought she was a chicken, which was followed by her having a generalized epileptic seizure.

“Clinically, we saw a lady who perspired profusely, trembled, blew up her cheeks, and ... seemed to imitate a chicken, [making noises] like clucking, cackling, and crowing like a rooster,” they say.

“After about 10 minutes she seemed to tighten her muscles for a few seconds, her face turned red and for a short time she didn’t react. These symptoms repeated themselves at intervals of a few minutes [and her] consciousness was fluctuating,” with the patient “disoriented in time and space.”

Lead author Dr Athena Beckers of University Psychiatric Centre, KU Leuven, Belgium, said in an interview with MediQuality: “With only 56 case descriptions in the medical literature from 1850 to the present day, the condition is rare. It amounts to about one description every 3 years.

“We suspect, however, that the delusion is not always noticed: the patient shows bizarre behaviour or makes animal sounds, it is probably often catalogued under the general term ‘psychosis’.”

Dr Beckers adds that it is important that the symptoms are recognised, because of the possible underlying causes which can include epilepsy. So this might require a different or complementary treatment “with, for example, antiepileptic drugs”.

“I myself have only seen this type of delusion once, but I ... heard anecdotal stories from other patients whose family member, for example with schizophrenia, sometimes thought he was a cow [during] ... a psychosis.

“After the publication of my article I was also contacted by someone who told me they had experienced the same thing 30 years ago – he thought he was a chicken.

“I think it’s a good thing that we psychiatrists are aware of the fact that clinical zoanthropy exists and may require additional research,” she observed.

Fortunately, this woman’s experience ended well. After about one year of disability, the patient was able to return to work progressively. Her mood remained stable and there were no more psychotic symptoms or any indication of epileptic episodes.
 

Such Delusions Are Rare 

Dr Georges Otte, a recently retired neuropsychiatrist who formerly worked at Ghent University, Belgium, gave his thoughts to Mediquality: “The interface between neurology and psychiatry ... is a fertile meadow on which many crops thrive. But it is in the darkest corners of psychosis that one finds the most bizarre and also rarest excesses.”

There are a number of delusions of identity, said Dr Otte.

These include Cotard’s syndrome, a rare condition marked by the false belief that the person or their body parts are dead, dying, or don’t exist, or Capgras delusion, where the affected person believes that a spouse or close family member has been replaced with an imposter. Delusions can also occur as a result of substance abuse, for example after using psilocybin (magic mushrooms), he added.

“Delusions in which patients are convinced of ‘shape shifting’ (man to animal) are quite rare,” Dr Otte observed.

“In the literature we know that lycanthropy [a person thinks he or she is turning into a werewolf],” has been reported, and has “apparently inspired many authors of horror stories,” he added.

“But it’s not every day that as a psychiatrist, you will encounter such an extreme psychotic depersonalization as someone turning into a chicken.”
 

This article first appeared on Medscape.com.

Research into the microbiome is yielding some positive new potential treatment options for Alzheimer’s disease, according to George T. Grossberg, MD.

“I think the growing focus on the gut-brain axis is opening doors to new Alzheimer’s disease and other brain disorders, and I think the first of a possible future generation of compounds for prevention or treatment of Alzheimer’s disease may indeed be emerging,” Dr. Grossberg said at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Focus on the microbiome and microbiota is “a really hot, really new, really emerging area,” said Dr. Grossberg, professor in the department of psychiatry & behavioral neuroscience at Saint Louis University. But the microbiota, which is the microorganisms within a specific organ such as the colon, is sometimes confused with the microbiome – which is defined as all of the bacteria, viruses, fungi and other microorganisms within a habitat as well as their genomes and the environment around them. “These are often used interchangeably, but they’re not the same,” Dr. Grossberg said at the meeting, presented by Global Academy for Medical Education.

A person’s microbiome is unique to them, and nearly all of the microbiome is contained in the gut. A reduction in diversity of the microbiota in the digestive system has been linked to a wide variety of diseases, Dr. Grossberg explained. Inflammatory diseases, asthma, diabetes, obesity, and allergies are all conditions that have been linked to reduced microbiota diversity. Conversely, a microbial imbalance or dysbiosis has been implicated in anxiety and/or depression, dementia, and certain cancers, he noted.

Bacteria that positively affect the microbiome come from two main genera: Lactobacillus and Bifidobacterium. Factors such as diet, medications, geography, stage of life, birthing process, infant feeding method, and stress can all affect a person’s microbiome. “We’re all beginning to understand that trying to manage or trying to diversify, trying to manipulate the microbiota may have a lot of remote effects – even effects on weight or diabetes, or other disorders,” Dr. Grossberg said.

Fecal microbiota transplantation (FMT), or the process of administering a donor’s fecal matter into a recipient’s intestinal tract, has proved beneficial in improving the health of patients suffering from recurrent Clostridioides difficile infection. A recent Harvard Health Letter, written by Jessica Allegretti, MD, MPH, observed that FMT is standard of care for patients with C. diff, and the procedure has a success rate of between 80% and 90%.

“It shows us very directly, in a very practical way, how addressing the dysbiosis – the imbalance of the gut microbiome – by infusing healthy bacteria may make a potential lifesaving difference,” Dr. Grossberg said.

Research is beginning to show that the link between gut microbiota and health extends to Alzheimer’s disease as well. Within the last few years, “we’ve started to understand that the microbial diversity in Alzheimer’s disease versus healthy age-matched controls is decreased,” Dr. Grossberg said.

In a study published by Nicholas M. Vogt and colleagues, there was decreased fecal microbial diversity among individuals with Alzheimer’s, compared with healthy individuals matched for age. Another study by Ping Liu, PhD, and colleagues found that patients with Alzheimer’s disease had decreased fecal microbial diversity, compared with individuals who had pre-onset amnestic mild cognitive impairment and normal cognition.

Dr. Grossberg noted that, while these studies do not prove that less fecal microbial diversity is responsible for mild cognitive impairment or Alzheimer’s disease, “it makes us think that, maybe, there’s a contributing factor.”

“What happens with the dysbiosis of the gut microbiome is increased permeability of the epithelial area of the gut, which can then lead to the gut-brain axis dysregulation and may in fact allow the selective entry of bacteria into the central nervous system because the blood-brain barrier comes to be dysfunctional,” he said.

Early evidence suggests that the gut-brain axis can affect cognition. In an animal model study, transferring the microbiota of a mouse with Alzheimer’s disease to one that had been bred to be germ-free resulted in cognitive decline – but there was no cognitive decline for germ-free mice that received a microbiota transplant from a mouse in a healthy control group. Results from another animal study showed that transferring healthy microbiota from a mouse model into a mouse with Alzheimer’s disease reduces amyloid and tau pathology. “The conclusions of these studies seems to be that microbiota mediated intestinal and systemic immune changes or aberrations seem to contribute to the pathogenesis of Alzheimer’s disease in these mouse models,” Dr. Grossberg said. “Consequently, restoring the gut microbial homeostasis may have beneficial effects on Alzheimer’s disease treatment.”

Periodontal disease also might be linked to Alzheimer’s disease, Dr. Grossberg said. Several studies have shown gingipains secreted from Porphyromonas gingivalis, which contribute to inflammation in the brain, have been found in cadavers of patients with Alzheimer’s disease (Sci Adv. 2019 Jan 23;5[1]:eaau3333). “There’s reason to think that the same changes may be occurring in the human brain with periodontal disease,” he said.

The relationship also might extend to the gut microbiota and the central nervous system. “There seems to be a direct communication, a direct relationship between normal gut physiology and healthy central nervous system functioning, and then, when you have abnormal gut function, it may result in a variety of abnormal central nervous system functions,” Dr. Grossberg said.

Studies that have examined a relationship between Alzheimer’s disease and gut microbiota have highlighted the potential of probiotics and prebiotics as a method of restoring the gut microbiota (Aging [Albany NY]. 2020 Mar 31; 12[6]:5539-50). Probiotics are popularly sold in health food aisles of grocery stores, and prebiotics are available in foods such as yogurts, tempeh, sauerkraut, and kimchi, as well as in drinks such as Kombucha tea. The effectiveness of probiotics and prebiotics also are being examined in randomized, controlled trials in patients with mild cognitive decline and mild Alzheimer’s disease, Dr. Grossberg said. One therapy, Sodium oligomannate, a marine algae–derived oral oligosaccharide, has shown effectiveness in remodeling gut microbiota and has been approved in China to treat patients with mild or moderate Alzheimer’s disease. Currently, no approved gut microbiota therapies are approved in the United States to treat Alzheimer’s disease; however, encouraging use of a prebiotic, a probiotic, or a Mediterranean diet is something clinicians might want to consider for their patients.

“The fact that we’re studying these things has really led to the notion that it may not be a bad idea for people to consume these healthy bacteria in later life, either as a way to prevent or delay, or to treat Alzheimer’s disease,” Dr. Grossberg said. “There’s really no downside.”

Global Academy and this news organization are owned by the same parent company. Dr. Grossberg reported that he is a consultant for Acadia, Alkahest, Avanir, Axsome, Biogen, BioXcel, Karuna, Lundbeck, Otsuka, Roche, and Takeda; receives research support from the National Institute on Aging, Janssen, and Roche; performs safety monitoring for EryDel, Merck, and Newron; and serves on data monitoring committees for Avanex and ITI Therapeutics.

Research into the microbiome is yielding some positive new potential treatment options for Alzheimer’s disease, according to George T. Grossberg, MD.

“I think the growing focus on the gut-brain axis is opening doors to new Alzheimer’s disease and other brain disorders, and I think the first of a possible future generation of compounds for prevention or treatment of Alzheimer’s disease may indeed be emerging,” Dr. Grossberg said at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Focus on the microbiome and microbiota is “a really hot, really new, really emerging area,” said Dr. Grossberg, professor in the department of psychiatry & behavioral neuroscience at Saint Louis University. But the microbiota, which is the microorganisms within a specific organ such as the colon, is sometimes confused with the microbiome – which is defined as all of the bacteria, viruses, fungi and other microorganisms within a habitat as well as their genomes and the environment around them. “These are often used interchangeably, but they’re not the same,” Dr. Grossberg said at the meeting, presented by Global Academy for Medical Education.

A person’s microbiome is unique to them, and nearly all of the microbiome is contained in the gut. A reduction in diversity of the microbiota in the digestive system has been linked to a wide variety of diseases, Dr. Grossberg explained. Inflammatory diseases, asthma, diabetes, obesity, and allergies are all conditions that have been linked to reduced microbiota diversity. Conversely, a microbial imbalance or dysbiosis has been implicated in anxiety and/or depression, dementia, and certain cancers, he noted.

Bacteria that positively affect the microbiome come from two main genera: Lactobacillus and Bifidobacterium. Factors such as diet, medications, geography, stage of life, birthing process, infant feeding method, and stress can all affect a person’s microbiome. “We’re all beginning to understand that trying to manage or trying to diversify, trying to manipulate the microbiota may have a lot of remote effects – even effects on weight or diabetes, or other disorders,” Dr. Grossberg said.

Fecal microbiota transplantation (FMT), or the process of administering a donor’s fecal matter into a recipient’s intestinal tract, has proved beneficial in improving the health of patients suffering from recurrent Clostridioides difficile infection. A recent Harvard Health Letter, written by Jessica Allegretti, MD, MPH, observed that FMT is standard of care for patients with C. diff, and the procedure has a success rate of between 80% and 90%.

“It shows us very directly, in a very practical way, how addressing the dysbiosis – the imbalance of the gut microbiome – by infusing healthy bacteria may make a potential lifesaving difference,” Dr. Grossberg said.

Research is beginning to show that the link between gut microbiota and health extends to Alzheimer’s disease as well. Within the last few years, “we’ve started to understand that the microbial diversity in Alzheimer’s disease versus healthy age-matched controls is decreased,” Dr. Grossberg said.

In a study published by Nicholas M. Vogt and colleagues, there was decreased fecal microbial diversity among individuals with Alzheimer’s, compared with healthy individuals matched for age. Another study by Ping Liu, PhD, and colleagues found that patients with Alzheimer’s disease had decreased fecal microbial diversity, compared with individuals who had pre-onset amnestic mild cognitive impairment and normal cognition.

Dr. Grossberg noted that, while these studies do not prove that less fecal microbial diversity is responsible for mild cognitive impairment or Alzheimer’s disease, “it makes us think that, maybe, there’s a contributing factor.”

“What happens with the dysbiosis of the gut microbiome is increased permeability of the epithelial area of the gut, which can then lead to the gut-brain axis dysregulation and may in fact allow the selective entry of bacteria into the central nervous system because the blood-brain barrier comes to be dysfunctional,” he said.

Early evidence suggests that the gut-brain axis can affect cognition. In an animal model study, transferring the microbiota of a mouse with Alzheimer’s disease to one that had been bred to be germ-free resulted in cognitive decline – but there was no cognitive decline for germ-free mice that received a microbiota transplant from a mouse in a healthy control group. Results from another animal study showed that transferring healthy microbiota from a mouse model into a mouse with Alzheimer’s disease reduces amyloid and tau pathology. “The conclusions of these studies seems to be that microbiota mediated intestinal and systemic immune changes or aberrations seem to contribute to the pathogenesis of Alzheimer’s disease in these mouse models,” Dr. Grossberg said. “Consequently, restoring the gut microbial homeostasis may have beneficial effects on Alzheimer’s disease treatment.”

Periodontal disease also might be linked to Alzheimer’s disease, Dr. Grossberg said. Several studies have shown gingipains secreted from Porphyromonas gingivalis, which contribute to inflammation in the brain, have been found in cadavers of patients with Alzheimer’s disease (Sci Adv. 2019 Jan 23;5[1]:eaau3333). “There’s reason to think that the same changes may be occurring in the human brain with periodontal disease,” he said.

The relationship also might extend to the gut microbiota and the central nervous system. “There seems to be a direct communication, a direct relationship between normal gut physiology and healthy central nervous system functioning, and then, when you have abnormal gut function, it may result in a variety of abnormal central nervous system functions,” Dr. Grossberg said.

Studies that have examined a relationship between Alzheimer’s disease and gut microbiota have highlighted the potential of probiotics and prebiotics as a method of restoring the gut microbiota (Aging [Albany NY]. 2020 Mar 31; 12[6]:5539-50). Probiotics are popularly sold in health food aisles of grocery stores, and prebiotics are available in foods such as yogurts, tempeh, sauerkraut, and kimchi, as well as in drinks such as Kombucha tea. The effectiveness of probiotics and prebiotics also are being examined in randomized, controlled trials in patients with mild cognitive decline and mild Alzheimer’s disease, Dr. Grossberg said. One therapy, Sodium oligomannate, a marine algae–derived oral oligosaccharide, has shown effectiveness in remodeling gut microbiota and has been approved in China to treat patients with mild or moderate Alzheimer’s disease. Currently, no approved gut microbiota therapies are approved in the United States to treat Alzheimer’s disease; however, encouraging use of a prebiotic, a probiotic, or a Mediterranean diet is something clinicians might want to consider for their patients.

“The fact that we’re studying these things has really led to the notion that it may not be a bad idea for people to consume these healthy bacteria in later life, either as a way to prevent or delay, or to treat Alzheimer’s disease,” Dr. Grossberg said. “There’s really no downside.”

Global Academy and this news organization are owned by the same parent company. Dr. Grossberg reported that he is a consultant for Acadia, Alkahest, Avanir, Axsome, Biogen, BioXcel, Karuna, Lundbeck, Otsuka, Roche, and Takeda; receives research support from the National Institute on Aging, Janssen, and Roche; performs safety monitoring for EryDel, Merck, and Newron; and serves on data monitoring committees for Avanex and ITI Therapeutics.

Research into the microbiome is yielding some positive new potential treatment options for Alzheimer’s disease, according to George T. Grossberg, MD.

“I think the growing focus on the gut-brain axis is opening doors to new Alzheimer’s disease and other brain disorders, and I think the first of a possible future generation of compounds for prevention or treatment of Alzheimer’s disease may indeed be emerging,” Dr. Grossberg said at a virtual meeting presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

Focus on the microbiome and microbiota is “a really hot, really new, really emerging area,” said Dr. Grossberg, professor in the department of psychiatry & behavioral neuroscience at Saint Louis University. But the microbiota, which is the microorganisms within a specific organ such as the colon, is sometimes confused with the microbiome – which is defined as all of the bacteria, viruses, fungi and other microorganisms within a habitat as well as their genomes and the environment around them. “These are often used interchangeably, but they’re not the same,” Dr. Grossberg said at the meeting, presented by Global Academy for Medical Education.

A person’s microbiome is unique to them, and nearly all of the microbiome is contained in the gut. A reduction in diversity of the microbiota in the digestive system has been linked to a wide variety of diseases, Dr. Grossberg explained. Inflammatory diseases, asthma, diabetes, obesity, and allergies are all conditions that have been linked to reduced microbiota diversity. Conversely, a microbial imbalance or dysbiosis has been implicated in anxiety and/or depression, dementia, and certain cancers, he noted.

Bacteria that positively affect the microbiome come from two main genera: Lactobacillus and Bifidobacterium. Factors such as diet, medications, geography, stage of life, birthing process, infant feeding method, and stress can all affect a person’s microbiome. “We’re all beginning to understand that trying to manage or trying to diversify, trying to manipulate the microbiota may have a lot of remote effects – even effects on weight or diabetes, or other disorders,” Dr. Grossberg said.

Fecal microbiota transplantation (FMT), or the process of administering a donor’s fecal matter into a recipient’s intestinal tract, has proved beneficial in improving the health of patients suffering from recurrent Clostridioides difficile infection. A recent Harvard Health Letter, written by Jessica Allegretti, MD, MPH, observed that FMT is standard of care for patients with C. diff, and the procedure has a success rate of between 80% and 90%.

“It shows us very directly, in a very practical way, how addressing the dysbiosis – the imbalance of the gut microbiome – by infusing healthy bacteria may make a potential lifesaving difference,” Dr. Grossberg said.

Research is beginning to show that the link between gut microbiota and health extends to Alzheimer’s disease as well. Within the last few years, “we’ve started to understand that the microbial diversity in Alzheimer’s disease versus healthy age-matched controls is decreased,” Dr. Grossberg said.

In a study published by Nicholas M. Vogt and colleagues, there was decreased fecal microbial diversity among individuals with Alzheimer’s, compared with healthy individuals matched for age. Another study by Ping Liu, PhD, and colleagues found that patients with Alzheimer’s disease had decreased fecal microbial diversity, compared with individuals who had pre-onset amnestic mild cognitive impairment and normal cognition.

Dr. Grossberg noted that, while these studies do not prove that less fecal microbial diversity is responsible for mild cognitive impairment or Alzheimer’s disease, “it makes us think that, maybe, there’s a contributing factor.”

“What happens with the dysbiosis of the gut microbiome is increased permeability of the epithelial area of the gut, which can then lead to the gut-brain axis dysregulation and may in fact allow the selective entry of bacteria into the central nervous system because the blood-brain barrier comes to be dysfunctional,” he said.

Early evidence suggests that the gut-brain axis can affect cognition. In an animal model study, transferring the microbiota of a mouse with Alzheimer’s disease to one that had been bred to be germ-free resulted in cognitive decline – but there was no cognitive decline for germ-free mice that received a microbiota transplant from a mouse in a healthy control group. Results from another animal study showed that transferring healthy microbiota from a mouse model into a mouse with Alzheimer’s disease reduces amyloid and tau pathology. “The conclusions of these studies seems to be that microbiota mediated intestinal and systemic immune changes or aberrations seem to contribute to the pathogenesis of Alzheimer’s disease in these mouse models,” Dr. Grossberg said. “Consequently, restoring the gut microbial homeostasis may have beneficial effects on Alzheimer’s disease treatment.”

Periodontal disease also might be linked to Alzheimer’s disease, Dr. Grossberg said. Several studies have shown gingipains secreted from Porphyromonas gingivalis, which contribute to inflammation in the brain, have been found in cadavers of patients with Alzheimer’s disease (Sci Adv. 2019 Jan 23;5[1]:eaau3333). “There’s reason to think that the same changes may be occurring in the human brain with periodontal disease,” he said.

The relationship also might extend to the gut microbiota and the central nervous system. “There seems to be a direct communication, a direct relationship between normal gut physiology and healthy central nervous system functioning, and then, when you have abnormal gut function, it may result in a variety of abnormal central nervous system functions,” Dr. Grossberg said.

Studies that have examined a relationship between Alzheimer’s disease and gut microbiota have highlighted the potential of probiotics and prebiotics as a method of restoring the gut microbiota (Aging [Albany NY]. 2020 Mar 31; 12[6]:5539-50). Probiotics are popularly sold in health food aisles of grocery stores, and prebiotics are available in foods such as yogurts, tempeh, sauerkraut, and kimchi, as well as in drinks such as Kombucha tea. The effectiveness of probiotics and prebiotics also are being examined in randomized, controlled trials in patients with mild cognitive decline and mild Alzheimer’s disease, Dr. Grossberg said. One therapy, Sodium oligomannate, a marine algae–derived oral oligosaccharide, has shown effectiveness in remodeling gut microbiota and has been approved in China to treat patients with mild or moderate Alzheimer’s disease. Currently, no approved gut microbiota therapies are approved in the United States to treat Alzheimer’s disease; however, encouraging use of a prebiotic, a probiotic, or a Mediterranean diet is something clinicians might want to consider for their patients.

“The fact that we’re studying these things has really led to the notion that it may not be a bad idea for people to consume these healthy bacteria in later life, either as a way to prevent or delay, or to treat Alzheimer’s disease,” Dr. Grossberg said. “There’s really no downside.”

Global Academy and this news organization are owned by the same parent company. Dr. Grossberg reported that he is a consultant for Acadia, Alkahest, Avanir, Axsome, Biogen, BioXcel, Karuna, Lundbeck, Otsuka, Roche, and Takeda; receives research support from the National Institute on Aging, Janssen, and Roche; performs safety monitoring for EryDel, Merck, and Newron; and serves on data monitoring committees for Avanex and ITI Therapeutics.

Researchers are making headway in developing a blood test for the presence of tau, one of the hallmarks of Alzheimer’s disease .

In one new development, experts at the University of California, San Francisco (UCSF) compared phosphorylated-tau181 (P-tau181) to a related form of tau called P-tau217 to determine which can best identify individuals with Alzheimer’s disease.

Results showed that the two biomarkers were similar overall, but P-tau 217 had a slight edge in terms of accuracy. Importantly, both tau isoforms distinguished frontotemporal lobar degeneration (FTLD).

“These new blood tests for P-tau are going to be really exciting because they will improve our ability to simply and inexpensively assess whether someone is at high risk for having Alzheimer’s disease,” said study author Adam L. Boxer, MD, PhD, professor in UCSF’s department of neurology.

With the approval of the first disease-modifying therapy for Alzheimer’s disease possibly around the corner, developing an accurate diagnostic blood test for this condition is even more urgent, added Dr. Boxer, who is also director of UCSF’s Neurosciences Clinical Research Unit and AD and FTD Clinical Trials Program.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.
 

Important implications

Currently, the only approved Alzheimer’s disease biomarkers are expensive positron emission tomography (PET) scans using agents that detect tau or amyloid, another hallmark Alzheimer’s disease protein, and cerebrospinal fluid levels of amyloid and tau, the measurement of which entails invasive lumbar puncture procedures. This limits the ability to easily confirm the underlying cause of dementia or cognitive impairment, which “obviously has important prognostic and therapeutic implications,” said Dr. Boxer.

Having a plasma biomarker, especially for tau, would be extremely useful. Patients with increased tau in the brain tend to exhibit Alzheimer’s disease symptoms while those with amyloid plaques do not always have clear signs, at least not immediately. “We think that P-tau is probably a better measure because it is much more closely related to symptoms of disease,” said Dr. Boxer.

Earlier this year, he and colleagues published a study in Nature Medicine showing that P-tau181 is more than three times as high in individuals with Alzheimer’s disease compared with healthy elderly people. It also differentiated Alzheimer’s disease from frontotemporal dementia (FTD). “We found that P-tau 181 was almost as good as a PET scan or lumbar puncture at identifying individuals with Alzheimer’s disease pathology in the brain,” said Dr. Boxer.

They next wanted to assess how well P-tau 217 held up as a possible biomarker.

The new retrospective study was composed of 210 participants: 37 who acted as healthy controls, 99 who had FTLD, 39 who had Alzheimer’s disease, and 35 who had mild cognitive impairment.
 

More accurate test

Results showed that plasma P-tau217 was increased 5.7-fold in the participants with Alzheimer’s disease compared with the healthy controls group, and increased fivefold compared with those who had FTLD (both comparisons, P < .001).

The increase in plasma P-tau181 was lower. It was increased only 4.5-times in participants with Alzheimer’s disease compared with the healthy controls and 3.8-times relative to those with FTLD (both, P < .001). In addition, P-tau217 was potentially superior in predicting whether a person had a tau positive FTP-PET brain scan.

“This newer P-tau 217 test produces very similar results to the previous test we published [on P-tau181], but might be incrementally better or slightly more accurate, and even more closely related to the signal you get with a tau PET scan,” Dr. Boxer said.

The researchers are now examining these issues in a larger group of participants (N = 617). Results for those analyses are expected to be published soon. In addition to tau and amyloid markers, the researchers are examining another potential biomarker of neurodegeneration: the triple protein neurofilament light chain.

It’s too early to say which biomarker or biomarkers will prove to be the most useful in diagnosing Alzheimer’s disease, Dr. Boxer noted. “It’s an open question whether it will be necessary to measure multiple P-taus plus beta amyloid plus neurofilament, or maybe just measuring one P-tau level will be sufficient,” he said.

Upcoming therapy?

Having a test that verifies Alzheimer’s disease is becoming all the more important now that a therapy might soon be available. Massachusetts-based biotech company Biogen has submitted aducanumab, a monoclonal antibody that targets amyloid-beta (Abeta), to the Food and Drug Administration for approval. Should that move forward, aducanumab would be the first disease-modifying therapy for Alzheimer’s disease.

“If that’s the case, it will be even more important to have simple ways to screen people, to see if they might eventually be eligible for treatment,” said Dr. Boxer. Even if the drug isn’t approved, many patients simply want to know what is causing their cognitive problems, he added. Knowing they have Alzheimer’s disease might impact their life planning. If they have mild symptoms, interventions such as exercise and reducing cardiovascular risk could improve their overall health and quality of life, he said.

If individuals have another type of dementia, such as FTLD, that, too, might determine a different approach. Some forms of FTLD are caused by “completely different biological processes,” which are now being studied, Dr. Boxer said. So knowing that patients have this condition would allow them to participate in relevant clinical trials.

Exciting aspect

Having a tau blood test will also help those in underserviced and minority communities who can’t easily access memory specialists, Dr. Boxer noted. “It might allow them to access care, and get help much more easily, and that is a really exciting aspect of this new technology,” he said. It’s not clear when such blood tests will be on the market, although many companies are “scrambling” to make them available, said Dr. Boxer.

P-tau217 also holds promise as a marker for early Alzheimer’s disease pathology, according to another study presented at AAIC 2020. A Swedish research team measured P-tau217 in more than 1,000 participants, including those who were unimpaired and those with mild cognitive impairment, Alzheimer’s disease dementia, or non-Alzheimer’s disease neurodegenerative diseases.

Results showed that plasma P-tau217 levels increase in early stages of Alzheimer’s disease when insoluble tau aggregates are not yet detectable with PET. They also predict subsequent increases in tau-PET, as well as conversion to Alzheimer’s disease dementia.

‘Incredible breakthrough’

Commenting on the research, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, called the study amazing and “an incredible breakthrough.

“Researchers are able to detect disease up to 20 years before symptoms. The blood test has very good characteristics in terms of sensitivity and specificity. It correlates with the spinal fluid, it’s better than the PET imaging, it correlates with the amyloid test, and the results are being confirmed in many different cohorts,” said Dr. Fillit, who was not involved with the research.

A tau blood test, especially for P-tau 217, has the potential to be as important to determining dementia risk as cholesterol is to gauging heart disease risk, he added.

Having a tau blood test will “make our clinical trials much more precise and more efficient and reduce costs tremendously,” Dr. Fillit said, adding that he thinks tau blood tests might come to market as early as within a year.

Also commenting on the research, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said the new studies illustrate the rapid progress being made “in the blood biomarker space.”

Even 5 years ago, researchers would “never have thought” that blood biomarkers could be used as a tool to detect brain changes related to Alzheimer’s disease, said Dr. Edelmayer.

These new studies are “filling a gap in our understanding around tau” in Alzheimer’s disease and other neurodegenerative diseases, she said. “Being able to distinguish between diseases is going to be very, very crucial for clinicians in the future,” she added.

Dr. Edelmayer foresees that in the future there will be a panel of blood biomarkers in addition to imaging tests to help clinicians make an accurate diagnosis.

The study was supported by the National Institutes of Health and the Tau Research Consortium. Dr. Boxer disclosed that the blood p-tau test was done as part of a research collaboration between UCSF and Eli Lilly. Dr. Fillit and Dr. Edelmayer have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Researchers are making headway in developing a blood test for the presence of tau, one of the hallmarks of Alzheimer’s disease .

In one new development, experts at the University of California, San Francisco (UCSF) compared phosphorylated-tau181 (P-tau181) to a related form of tau called P-tau217 to determine which can best identify individuals with Alzheimer’s disease.

Results showed that the two biomarkers were similar overall, but P-tau 217 had a slight edge in terms of accuracy. Importantly, both tau isoforms distinguished frontotemporal lobar degeneration (FTLD).

“These new blood tests for P-tau are going to be really exciting because they will improve our ability to simply and inexpensively assess whether someone is at high risk for having Alzheimer’s disease,” said study author Adam L. Boxer, MD, PhD, professor in UCSF’s department of neurology.

With the approval of the first disease-modifying therapy for Alzheimer’s disease possibly around the corner, developing an accurate diagnostic blood test for this condition is even more urgent, added Dr. Boxer, who is also director of UCSF’s Neurosciences Clinical Research Unit and AD and FTD Clinical Trials Program.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.
 

Important implications

Currently, the only approved Alzheimer’s disease biomarkers are expensive positron emission tomography (PET) scans using agents that detect tau or amyloid, another hallmark Alzheimer’s disease protein, and cerebrospinal fluid levels of amyloid and tau, the measurement of which entails invasive lumbar puncture procedures. This limits the ability to easily confirm the underlying cause of dementia or cognitive impairment, which “obviously has important prognostic and therapeutic implications,” said Dr. Boxer.

Having a plasma biomarker, especially for tau, would be extremely useful. Patients with increased tau in the brain tend to exhibit Alzheimer’s disease symptoms while those with amyloid plaques do not always have clear signs, at least not immediately. “We think that P-tau is probably a better measure because it is much more closely related to symptoms of disease,” said Dr. Boxer.

Earlier this year, he and colleagues published a study in Nature Medicine showing that P-tau181 is more than three times as high in individuals with Alzheimer’s disease compared with healthy elderly people. It also differentiated Alzheimer’s disease from frontotemporal dementia (FTD). “We found that P-tau 181 was almost as good as a PET scan or lumbar puncture at identifying individuals with Alzheimer’s disease pathology in the brain,” said Dr. Boxer.

They next wanted to assess how well P-tau 217 held up as a possible biomarker.

The new retrospective study was composed of 210 participants: 37 who acted as healthy controls, 99 who had FTLD, 39 who had Alzheimer’s disease, and 35 who had mild cognitive impairment.
 

More accurate test

Results showed that plasma P-tau217 was increased 5.7-fold in the participants with Alzheimer’s disease compared with the healthy controls group, and increased fivefold compared with those who had FTLD (both comparisons, P < .001).

The increase in plasma P-tau181 was lower. It was increased only 4.5-times in participants with Alzheimer’s disease compared with the healthy controls and 3.8-times relative to those with FTLD (both, P < .001). In addition, P-tau217 was potentially superior in predicting whether a person had a tau positive FTP-PET brain scan.

“This newer P-tau 217 test produces very similar results to the previous test we published [on P-tau181], but might be incrementally better or slightly more accurate, and even more closely related to the signal you get with a tau PET scan,” Dr. Boxer said.

The researchers are now examining these issues in a larger group of participants (N = 617). Results for those analyses are expected to be published soon. In addition to tau and amyloid markers, the researchers are examining another potential biomarker of neurodegeneration: the triple protein neurofilament light chain.

It’s too early to say which biomarker or biomarkers will prove to be the most useful in diagnosing Alzheimer’s disease, Dr. Boxer noted. “It’s an open question whether it will be necessary to measure multiple P-taus plus beta amyloid plus neurofilament, or maybe just measuring one P-tau level will be sufficient,” he said.

Upcoming therapy?

Having a test that verifies Alzheimer’s disease is becoming all the more important now that a therapy might soon be available. Massachusetts-based biotech company Biogen has submitted aducanumab, a monoclonal antibody that targets amyloid-beta (Abeta), to the Food and Drug Administration for approval. Should that move forward, aducanumab would be the first disease-modifying therapy for Alzheimer’s disease.

“If that’s the case, it will be even more important to have simple ways to screen people, to see if they might eventually be eligible for treatment,” said Dr. Boxer. Even if the drug isn’t approved, many patients simply want to know what is causing their cognitive problems, he added. Knowing they have Alzheimer’s disease might impact their life planning. If they have mild symptoms, interventions such as exercise and reducing cardiovascular risk could improve their overall health and quality of life, he said.

If individuals have another type of dementia, such as FTLD, that, too, might determine a different approach. Some forms of FTLD are caused by “completely different biological processes,” which are now being studied, Dr. Boxer said. So knowing that patients have this condition would allow them to participate in relevant clinical trials.

Exciting aspect

Having a tau blood test will also help those in underserviced and minority communities who can’t easily access memory specialists, Dr. Boxer noted. “It might allow them to access care, and get help much more easily, and that is a really exciting aspect of this new technology,” he said. It’s not clear when such blood tests will be on the market, although many companies are “scrambling” to make them available, said Dr. Boxer.

P-tau217 also holds promise as a marker for early Alzheimer’s disease pathology, according to another study presented at AAIC 2020. A Swedish research team measured P-tau217 in more than 1,000 participants, including those who were unimpaired and those with mild cognitive impairment, Alzheimer’s disease dementia, or non-Alzheimer’s disease neurodegenerative diseases.

Results showed that plasma P-tau217 levels increase in early stages of Alzheimer’s disease when insoluble tau aggregates are not yet detectable with PET. They also predict subsequent increases in tau-PET, as well as conversion to Alzheimer’s disease dementia.

‘Incredible breakthrough’

Commenting on the research, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, called the study amazing and “an incredible breakthrough.

“Researchers are able to detect disease up to 20 years before symptoms. The blood test has very good characteristics in terms of sensitivity and specificity. It correlates with the spinal fluid, it’s better than the PET imaging, it correlates with the amyloid test, and the results are being confirmed in many different cohorts,” said Dr. Fillit, who was not involved with the research.

A tau blood test, especially for P-tau 217, has the potential to be as important to determining dementia risk as cholesterol is to gauging heart disease risk, he added.

Having a tau blood test will “make our clinical trials much more precise and more efficient and reduce costs tremendously,” Dr. Fillit said, adding that he thinks tau blood tests might come to market as early as within a year.

Also commenting on the research, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said the new studies illustrate the rapid progress being made “in the blood biomarker space.”

Even 5 years ago, researchers would “never have thought” that blood biomarkers could be used as a tool to detect brain changes related to Alzheimer’s disease, said Dr. Edelmayer.

These new studies are “filling a gap in our understanding around tau” in Alzheimer’s disease and other neurodegenerative diseases, she said. “Being able to distinguish between diseases is going to be very, very crucial for clinicians in the future,” she added.

Dr. Edelmayer foresees that in the future there will be a panel of blood biomarkers in addition to imaging tests to help clinicians make an accurate diagnosis.

The study was supported by the National Institutes of Health and the Tau Research Consortium. Dr. Boxer disclosed that the blood p-tau test was done as part of a research collaboration between UCSF and Eli Lilly. Dr. Fillit and Dr. Edelmayer have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Researchers are making headway in developing a blood test for the presence of tau, one of the hallmarks of Alzheimer’s disease .

In one new development, experts at the University of California, San Francisco (UCSF) compared phosphorylated-tau181 (P-tau181) to a related form of tau called P-tau217 to determine which can best identify individuals with Alzheimer’s disease.

Results showed that the two biomarkers were similar overall, but P-tau 217 had a slight edge in terms of accuracy. Importantly, both tau isoforms distinguished frontotemporal lobar degeneration (FTLD).

“These new blood tests for P-tau are going to be really exciting because they will improve our ability to simply and inexpensively assess whether someone is at high risk for having Alzheimer’s disease,” said study author Adam L. Boxer, MD, PhD, professor in UCSF’s department of neurology.

With the approval of the first disease-modifying therapy for Alzheimer’s disease possibly around the corner, developing an accurate diagnostic blood test for this condition is even more urgent, added Dr. Boxer, who is also director of UCSF’s Neurosciences Clinical Research Unit and AD and FTD Clinical Trials Program.

The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference.
 

Important implications

Currently, the only approved Alzheimer’s disease biomarkers are expensive positron emission tomography (PET) scans using agents that detect tau or amyloid, another hallmark Alzheimer’s disease protein, and cerebrospinal fluid levels of amyloid and tau, the measurement of which entails invasive lumbar puncture procedures. This limits the ability to easily confirm the underlying cause of dementia or cognitive impairment, which “obviously has important prognostic and therapeutic implications,” said Dr. Boxer.

Having a plasma biomarker, especially for tau, would be extremely useful. Patients with increased tau in the brain tend to exhibit Alzheimer’s disease symptoms while those with amyloid plaques do not always have clear signs, at least not immediately. “We think that P-tau is probably a better measure because it is much more closely related to symptoms of disease,” said Dr. Boxer.

Earlier this year, he and colleagues published a study in Nature Medicine showing that P-tau181 is more than three times as high in individuals with Alzheimer’s disease compared with healthy elderly people. It also differentiated Alzheimer’s disease from frontotemporal dementia (FTD). “We found that P-tau 181 was almost as good as a PET scan or lumbar puncture at identifying individuals with Alzheimer’s disease pathology in the brain,” said Dr. Boxer.

They next wanted to assess how well P-tau 217 held up as a possible biomarker.

The new retrospective study was composed of 210 participants: 37 who acted as healthy controls, 99 who had FTLD, 39 who had Alzheimer’s disease, and 35 who had mild cognitive impairment.
 

More accurate test

Results showed that plasma P-tau217 was increased 5.7-fold in the participants with Alzheimer’s disease compared with the healthy controls group, and increased fivefold compared with those who had FTLD (both comparisons, P < .001).

The increase in plasma P-tau181 was lower. It was increased only 4.5-times in participants with Alzheimer’s disease compared with the healthy controls and 3.8-times relative to those with FTLD (both, P < .001). In addition, P-tau217 was potentially superior in predicting whether a person had a tau positive FTP-PET brain scan.

“This newer P-tau 217 test produces very similar results to the previous test we published [on P-tau181], but might be incrementally better or slightly more accurate, and even more closely related to the signal you get with a tau PET scan,” Dr. Boxer said.

The researchers are now examining these issues in a larger group of participants (N = 617). Results for those analyses are expected to be published soon. In addition to tau and amyloid markers, the researchers are examining another potential biomarker of neurodegeneration: the triple protein neurofilament light chain.

It’s too early to say which biomarker or biomarkers will prove to be the most useful in diagnosing Alzheimer’s disease, Dr. Boxer noted. “It’s an open question whether it will be necessary to measure multiple P-taus plus beta amyloid plus neurofilament, or maybe just measuring one P-tau level will be sufficient,” he said.

Upcoming therapy?

Having a test that verifies Alzheimer’s disease is becoming all the more important now that a therapy might soon be available. Massachusetts-based biotech company Biogen has submitted aducanumab, a monoclonal antibody that targets amyloid-beta (Abeta), to the Food and Drug Administration for approval. Should that move forward, aducanumab would be the first disease-modifying therapy for Alzheimer’s disease.

“If that’s the case, it will be even more important to have simple ways to screen people, to see if they might eventually be eligible for treatment,” said Dr. Boxer. Even if the drug isn’t approved, many patients simply want to know what is causing their cognitive problems, he added. Knowing they have Alzheimer’s disease might impact their life planning. If they have mild symptoms, interventions such as exercise and reducing cardiovascular risk could improve their overall health and quality of life, he said.

If individuals have another type of dementia, such as FTLD, that, too, might determine a different approach. Some forms of FTLD are caused by “completely different biological processes,” which are now being studied, Dr. Boxer said. So knowing that patients have this condition would allow them to participate in relevant clinical trials.

Exciting aspect

Having a tau blood test will also help those in underserviced and minority communities who can’t easily access memory specialists, Dr. Boxer noted. “It might allow them to access care, and get help much more easily, and that is a really exciting aspect of this new technology,” he said. It’s not clear when such blood tests will be on the market, although many companies are “scrambling” to make them available, said Dr. Boxer.

P-tau217 also holds promise as a marker for early Alzheimer’s disease pathology, according to another study presented at AAIC 2020. A Swedish research team measured P-tau217 in more than 1,000 participants, including those who were unimpaired and those with mild cognitive impairment, Alzheimer’s disease dementia, or non-Alzheimer’s disease neurodegenerative diseases.

Results showed that plasma P-tau217 levels increase in early stages of Alzheimer’s disease when insoluble tau aggregates are not yet detectable with PET. They also predict subsequent increases in tau-PET, as well as conversion to Alzheimer’s disease dementia.

‘Incredible breakthrough’

Commenting on the research, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, called the study amazing and “an incredible breakthrough.

“Researchers are able to detect disease up to 20 years before symptoms. The blood test has very good characteristics in terms of sensitivity and specificity. It correlates with the spinal fluid, it’s better than the PET imaging, it correlates with the amyloid test, and the results are being confirmed in many different cohorts,” said Dr. Fillit, who was not involved with the research.

A tau blood test, especially for P-tau 217, has the potential to be as important to determining dementia risk as cholesterol is to gauging heart disease risk, he added.

Having a tau blood test will “make our clinical trials much more precise and more efficient and reduce costs tremendously,” Dr. Fillit said, adding that he thinks tau blood tests might come to market as early as within a year.

Also commenting on the research, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, said the new studies illustrate the rapid progress being made “in the blood biomarker space.”

Even 5 years ago, researchers would “never have thought” that blood biomarkers could be used as a tool to detect brain changes related to Alzheimer’s disease, said Dr. Edelmayer.

These new studies are “filling a gap in our understanding around tau” in Alzheimer’s disease and other neurodegenerative diseases, she said. “Being able to distinguish between diseases is going to be very, very crucial for clinicians in the future,” she added.

Dr. Edelmayer foresees that in the future there will be a panel of blood biomarkers in addition to imaging tests to help clinicians make an accurate diagnosis.

The study was supported by the National Institutes of Health and the Tau Research Consortium. Dr. Boxer disclosed that the blood p-tau test was done as part of a research collaboration between UCSF and Eli Lilly. Dr. Fillit and Dr. Edelmayer have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.