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Two deaths from liver failure linked to spinal muscular atrophy drug
, according to a statement issued by the drug›s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment›s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.
A version of this article first appeared on Medscape.com.
, according to a statement issued by the drug›s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment›s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.
A version of this article first appeared on Medscape.com.
, according to a statement issued by the drug›s manufacturer.
The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.
These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.
“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.
“While this is important safety information, it is not a new safety signal,” it adds.
Rare genetic disorder
SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.
Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.
Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.
The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.
“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.
Studies have suggested that the treatment›s effects persist more than 5 years after infusion.
Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.
The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.
That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.
None of the current trials will be affected by the two deaths reported this week, according to a Novartis spokesperson.
A version of this article first appeared on Medscape.com.
More evidence salt substitutes lower risk of CVD and death
Dietary salt substitutes not only lower blood pressure but also have a clear impact on hard clinical endpoints, lowering the risk of myocardial infarction (MI), stroke, and death from all causes and cardiovascular disease (CVD), a meta-analysis shows.
The blood pressure–mediated protective effects of salt substitutes on CVD and death are likely to apply to the roughly 1.28 billion people around the world who have high blood pressure, the researchers say.
“These findings are unlikely to reflect the play of chance and support the adoption of salt substitutes in clinical practice and public health policy as a strategy to reduce dietary sodium intake, increase dietary potassium intake, lower blood pressure, and prevent major cardiovascular events,” they write.
The study was published online in Heart.
Strong support for landmark study
In salt substitutes, a proportion of sodium chloride is replaced with potassium chloride. They are known to help lower blood pressure, but less is known about their impact on hard clinical endpoints, Maoyi Tian, PhD, with Harbin Medical University, China, and the George Institute for Global Health, Sydney, and colleagues note in their article.
In the landmark Salt Substitute and Stroke Study (SSaSS), salt substitutes cut the risk of MI, stroke, and early death, as reported previously by this news organization.
But SSaSS was conducted in China, and it was unclear whether these benefits would apply to people in other parts of the world.
To investigate, Dr. Tian and colleagues pooled data from 21 relevant parallel-group, step-wedge, or cluster randomized controlled trials published through August 2021, with 31,949 participants. The trials were conducted in Europe, the Western Pacific Region, the Americas, and South East Asia and reported the effect of a salt substitute on blood pressure or clinical outcomes.
A meta-analysis of blood pressure data from 19 trials that included 29,528 participants showed that salt substitutes lowered systolic blood pressure (SBP) by 4.61 mm Hg (95% confidence interval, −6.07 to −3.14) and diastolic blood pressure (DBP) by 1.61 mm Hg (95% CI, −2.42 to −0.79).
The proportion of sodium chloride in the salt substitutes varied from 33% to 75%; the proportion of potassium ranged from 25% to 65%.
Each 10% lower proportion of sodium chloride in the salt substitute was associated with a 1.53 mm Hg (95% CI, −3.02 to −0.03; P = .045) greater reduction in SBP and a 0.95 mm Hg (95% CI, −1.78 to −0.12; P = .025) greater reduction in DBP.
Reductions in blood pressure appeared consistent, irrespective of country, age, sex, history of high blood pressure, weight, baseline blood pressure, and baseline levels of urinary sodium and potassium.
Clear benefit on hard outcomes
Pooled data on clinical outcomes from five trials that included 24,306 participants, mostly from the SSaSS, showed clear protective effects of salt substitutes on total mortality (risk ratio, 0.89; 95% CI, 0.85-0.94), CV mortality (RR, 0.87; 95% CI, 0.81-0.94), and CV events (RR, 0.89; 95% CI, 0.85-0.94).
Dr. Tian and colleagues say that “broader population use of salt substitute is supported by the absence of any detectable adverse effect of salt substitutes on hyperkalemia in this review.”
They note, however, that all of the trials took “pragmatic steps to exclude participants at elevated risk of hyperkalemia, seeking to exclude those with chronic kidney disease or using medications that elevate serum potassium.”
Offering perspective on the study, Harlan Krumholz, MD, with Yale New Haven Hospital and Yale School of Medicine, both in New Haven, Conn., said it provides “useful information by bringing together the trial evidence on salt substitutes. The evidence is dominated by the SSaSS, but the others add context.”
Dr. Krumholz said that at this point, he thinks salt substitutes “could be included in recommendations to patients.”
“SSaSS was conducted in villages in China, so that is where the evidence is strongest and most relevant, but this is a low-cost and seemingly safe strategy that could be tried by anyone without contraindications, such as kidney disease or taking a potassium-sparing medication or potassium supplement,” Dr. Krumholz told this news organization.
Johanna Contreras, MD, heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, agrees that in the absence of contraindications, salt substitutes should be recommended.
“Americans put salt on everything and don’t even think about it. The salt substitutes are very helpful,” Dr. Contreras said in an interview.
“People who don’t have high blood pressure should limit salt intake, because what we have seen is that if you have high blood pressure in your family – even if you don’t have high blood pressure in your 20s or 30s – you’re likely to develop high blood pressure,” Dr. Contreras said.
“Therefore, it’s wise early on to start protecting yourself and using low salt and salt substitutes,” she added.
The study had no specific funding. Dr. Tian, Dr. Krumholz, and Dr. Contreras have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Dietary salt substitutes not only lower blood pressure but also have a clear impact on hard clinical endpoints, lowering the risk of myocardial infarction (MI), stroke, and death from all causes and cardiovascular disease (CVD), a meta-analysis shows.
The blood pressure–mediated protective effects of salt substitutes on CVD and death are likely to apply to the roughly 1.28 billion people around the world who have high blood pressure, the researchers say.
“These findings are unlikely to reflect the play of chance and support the adoption of salt substitutes in clinical practice and public health policy as a strategy to reduce dietary sodium intake, increase dietary potassium intake, lower blood pressure, and prevent major cardiovascular events,” they write.
The study was published online in Heart.
Strong support for landmark study
In salt substitutes, a proportion of sodium chloride is replaced with potassium chloride. They are known to help lower blood pressure, but less is known about their impact on hard clinical endpoints, Maoyi Tian, PhD, with Harbin Medical University, China, and the George Institute for Global Health, Sydney, and colleagues note in their article.
In the landmark Salt Substitute and Stroke Study (SSaSS), salt substitutes cut the risk of MI, stroke, and early death, as reported previously by this news organization.
But SSaSS was conducted in China, and it was unclear whether these benefits would apply to people in other parts of the world.
To investigate, Dr. Tian and colleagues pooled data from 21 relevant parallel-group, step-wedge, or cluster randomized controlled trials published through August 2021, with 31,949 participants. The trials were conducted in Europe, the Western Pacific Region, the Americas, and South East Asia and reported the effect of a salt substitute on blood pressure or clinical outcomes.
A meta-analysis of blood pressure data from 19 trials that included 29,528 participants showed that salt substitutes lowered systolic blood pressure (SBP) by 4.61 mm Hg (95% confidence interval, −6.07 to −3.14) and diastolic blood pressure (DBP) by 1.61 mm Hg (95% CI, −2.42 to −0.79).
The proportion of sodium chloride in the salt substitutes varied from 33% to 75%; the proportion of potassium ranged from 25% to 65%.
Each 10% lower proportion of sodium chloride in the salt substitute was associated with a 1.53 mm Hg (95% CI, −3.02 to −0.03; P = .045) greater reduction in SBP and a 0.95 mm Hg (95% CI, −1.78 to −0.12; P = .025) greater reduction in DBP.
Reductions in blood pressure appeared consistent, irrespective of country, age, sex, history of high blood pressure, weight, baseline blood pressure, and baseline levels of urinary sodium and potassium.
Clear benefit on hard outcomes
Pooled data on clinical outcomes from five trials that included 24,306 participants, mostly from the SSaSS, showed clear protective effects of salt substitutes on total mortality (risk ratio, 0.89; 95% CI, 0.85-0.94), CV mortality (RR, 0.87; 95% CI, 0.81-0.94), and CV events (RR, 0.89; 95% CI, 0.85-0.94).
Dr. Tian and colleagues say that “broader population use of salt substitute is supported by the absence of any detectable adverse effect of salt substitutes on hyperkalemia in this review.”
They note, however, that all of the trials took “pragmatic steps to exclude participants at elevated risk of hyperkalemia, seeking to exclude those with chronic kidney disease or using medications that elevate serum potassium.”
Offering perspective on the study, Harlan Krumholz, MD, with Yale New Haven Hospital and Yale School of Medicine, both in New Haven, Conn., said it provides “useful information by bringing together the trial evidence on salt substitutes. The evidence is dominated by the SSaSS, but the others add context.”
Dr. Krumholz said that at this point, he thinks salt substitutes “could be included in recommendations to patients.”
“SSaSS was conducted in villages in China, so that is where the evidence is strongest and most relevant, but this is a low-cost and seemingly safe strategy that could be tried by anyone without contraindications, such as kidney disease or taking a potassium-sparing medication or potassium supplement,” Dr. Krumholz told this news organization.
Johanna Contreras, MD, heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, agrees that in the absence of contraindications, salt substitutes should be recommended.
“Americans put salt on everything and don’t even think about it. The salt substitutes are very helpful,” Dr. Contreras said in an interview.
“People who don’t have high blood pressure should limit salt intake, because what we have seen is that if you have high blood pressure in your family – even if you don’t have high blood pressure in your 20s or 30s – you’re likely to develop high blood pressure,” Dr. Contreras said.
“Therefore, it’s wise early on to start protecting yourself and using low salt and salt substitutes,” she added.
The study had no specific funding. Dr. Tian, Dr. Krumholz, and Dr. Contreras have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Dietary salt substitutes not only lower blood pressure but also have a clear impact on hard clinical endpoints, lowering the risk of myocardial infarction (MI), stroke, and death from all causes and cardiovascular disease (CVD), a meta-analysis shows.
The blood pressure–mediated protective effects of salt substitutes on CVD and death are likely to apply to the roughly 1.28 billion people around the world who have high blood pressure, the researchers say.
“These findings are unlikely to reflect the play of chance and support the adoption of salt substitutes in clinical practice and public health policy as a strategy to reduce dietary sodium intake, increase dietary potassium intake, lower blood pressure, and prevent major cardiovascular events,” they write.
The study was published online in Heart.
Strong support for landmark study
In salt substitutes, a proportion of sodium chloride is replaced with potassium chloride. They are known to help lower blood pressure, but less is known about their impact on hard clinical endpoints, Maoyi Tian, PhD, with Harbin Medical University, China, and the George Institute for Global Health, Sydney, and colleagues note in their article.
In the landmark Salt Substitute and Stroke Study (SSaSS), salt substitutes cut the risk of MI, stroke, and early death, as reported previously by this news organization.
But SSaSS was conducted in China, and it was unclear whether these benefits would apply to people in other parts of the world.
To investigate, Dr. Tian and colleagues pooled data from 21 relevant parallel-group, step-wedge, or cluster randomized controlled trials published through August 2021, with 31,949 participants. The trials were conducted in Europe, the Western Pacific Region, the Americas, and South East Asia and reported the effect of a salt substitute on blood pressure or clinical outcomes.
A meta-analysis of blood pressure data from 19 trials that included 29,528 participants showed that salt substitutes lowered systolic blood pressure (SBP) by 4.61 mm Hg (95% confidence interval, −6.07 to −3.14) and diastolic blood pressure (DBP) by 1.61 mm Hg (95% CI, −2.42 to −0.79).
The proportion of sodium chloride in the salt substitutes varied from 33% to 75%; the proportion of potassium ranged from 25% to 65%.
Each 10% lower proportion of sodium chloride in the salt substitute was associated with a 1.53 mm Hg (95% CI, −3.02 to −0.03; P = .045) greater reduction in SBP and a 0.95 mm Hg (95% CI, −1.78 to −0.12; P = .025) greater reduction in DBP.
Reductions in blood pressure appeared consistent, irrespective of country, age, sex, history of high blood pressure, weight, baseline blood pressure, and baseline levels of urinary sodium and potassium.
Clear benefit on hard outcomes
Pooled data on clinical outcomes from five trials that included 24,306 participants, mostly from the SSaSS, showed clear protective effects of salt substitutes on total mortality (risk ratio, 0.89; 95% CI, 0.85-0.94), CV mortality (RR, 0.87; 95% CI, 0.81-0.94), and CV events (RR, 0.89; 95% CI, 0.85-0.94).
Dr. Tian and colleagues say that “broader population use of salt substitute is supported by the absence of any detectable adverse effect of salt substitutes on hyperkalemia in this review.”
They note, however, that all of the trials took “pragmatic steps to exclude participants at elevated risk of hyperkalemia, seeking to exclude those with chronic kidney disease or using medications that elevate serum potassium.”
Offering perspective on the study, Harlan Krumholz, MD, with Yale New Haven Hospital and Yale School of Medicine, both in New Haven, Conn., said it provides “useful information by bringing together the trial evidence on salt substitutes. The evidence is dominated by the SSaSS, but the others add context.”
Dr. Krumholz said that at this point, he thinks salt substitutes “could be included in recommendations to patients.”
“SSaSS was conducted in villages in China, so that is where the evidence is strongest and most relevant, but this is a low-cost and seemingly safe strategy that could be tried by anyone without contraindications, such as kidney disease or taking a potassium-sparing medication or potassium supplement,” Dr. Krumholz told this news organization.
Johanna Contreras, MD, heart failure and transplant cardiologist at the Mount Sinai Hospital, New York, agrees that in the absence of contraindications, salt substitutes should be recommended.
“Americans put salt on everything and don’t even think about it. The salt substitutes are very helpful,” Dr. Contreras said in an interview.
“People who don’t have high blood pressure should limit salt intake, because what we have seen is that if you have high blood pressure in your family – even if you don’t have high blood pressure in your 20s or 30s – you’re likely to develop high blood pressure,” Dr. Contreras said.
“Therefore, it’s wise early on to start protecting yourself and using low salt and salt substitutes,” she added.
The study had no specific funding. Dr. Tian, Dr. Krumholz, and Dr. Contreras have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Alzheimer’s disease: Alternative mechanisms make clinical progress
SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.
To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
Chasing the wrong target?
At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.
Later in the session,
One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.
After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
A diverse clinical pipeline
The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.
Targeting neuroinflammation
Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.
The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
Maintaining homeostatis
Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.
Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
Type 3 diabetes?
In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.
“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.
The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
Focusing on neurotoxic proteins
The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.
“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.
The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.
The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
Combination treatments for a complex disease
Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.
The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.
Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.
Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.
SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.
To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
Chasing the wrong target?
At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.
Later in the session,
One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.
After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
A diverse clinical pipeline
The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.
Targeting neuroinflammation
Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.
The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
Maintaining homeostatis
Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.
Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
Type 3 diabetes?
In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.
“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.
The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
Focusing on neurotoxic proteins
The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.
“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.
The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.
The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
Combination treatments for a complex disease
Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.
The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.
Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.
Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.
SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.
To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
Chasing the wrong target?
At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.
Later in the session,
One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.
After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
A diverse clinical pipeline
The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.
Targeting neuroinflammation
Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.
The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
Maintaining homeostatis
Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.
Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
Type 3 diabetes?
In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.
“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.
The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
Focusing on neurotoxic proteins
The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.
“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.
The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.
The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
Combination treatments for a complex disease
Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.
The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.
Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.
Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.
AT AAIC 2022
Federal Health Care Data Trends 2022
Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations.
In this issue:
- Vaccinations
- Mental Health and Related Disorders
- LGBTQ+ Veterans
- Military Sexual Trauma
- Sleep Disorders
- Respiratory Illnesses
- HIV Care in the VA
- Rheumatologic Diseases
- The Cancer-Obesity Connection
- Skin Health for Active-Duty Personnel
- Contraception
- Chronic Kidney Disease
- Cardiovascular Diseases
- Neurologic Disorders
- Hearing, Vision, and Balance
Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue:
Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN
Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations.
In this issue:
- Vaccinations
- Mental Health and Related Disorders
- LGBTQ+ Veterans
- Military Sexual Trauma
- Sleep Disorders
- Respiratory Illnesses
- HIV Care in the VA
- Rheumatologic Diseases
- The Cancer-Obesity Connection
- Skin Health for Active-Duty Personnel
- Contraception
- Chronic Kidney Disease
- Cardiovascular Diseases
- Neurologic Disorders
- Hearing, Vision, and Balance
Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue:
Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN
Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations.
In this issue:
- Vaccinations
- Mental Health and Related Disorders
- LGBTQ+ Veterans
- Military Sexual Trauma
- Sleep Disorders
- Respiratory Illnesses
- HIV Care in the VA
- Rheumatologic Diseases
- The Cancer-Obesity Connection
- Skin Health for Active-Duty Personnel
- Contraception
- Chronic Kidney Disease
- Cardiovascular Diseases
- Neurologic Disorders
- Hearing, Vision, and Balance
Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue:
Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN
The role of aspirin today
This transcript has been edited for clarity.
Dear colleagues, I am Christoph Diener from the faculty of medicine at the University of Duisburg-Essen in Germany.
Usually in this video series, I report on interesting scientific studies in the field of neurology published in the last month. But I have to admit, June was a lousy month for new science in neurology. Therefore, this month I’d like to take a different approach and tell you about a very interesting, old drug.
We are celebrating the 125th anniversary of aspirin. Aspirin was first synthesized in Wuppertal, Germany, a city which is only 40 km from my location, by Felix Hoffmann. Hoffmann was searching for a new drug for his father who suffered from severe joint pain, and the available drugs at that time had terrible adverse events. This prompted him to work on a new drug, which was later called aspirin acetylsalicylic acid.
Aspirin has been used very successfully to the present day as therapy for joint pain or arthritis. But as you know, it’s also effective in headaches, in particular, tension-type headache. I think it’s one of the most used drugs in the world for the treatment of acute migraine attacks.
It’s also available in some European countries in intravenous form for the treatment of severe migraine attacks or in the emergency room, and it’s as effective as subcutaneous sumatriptan. It’s also an effective migraine preventive drug in a dose of 300 mg/d.
Discovering aspirin’s antiplatelet activity
There was an interesting observation by a dentist in the 1930s, who noted bleeding when he extracted teeth in people who took aspirin for joint pain. When he started to ask his patients about possible bleeding complications and vascular events, he observed that people who took aspirin didn’t have coronary myocardial infarctions.
It took a long time for people to discover that aspirin is not only a pain medication but also an antiplatelet agent. The first randomized study that showed that aspirin is effective in secondary prevention after myocardial infarction was published in 1974 in The New England Journal of Medicine. In 1980, aspirin was approved by the U.S. Food and Drug Administration for the secondary prevention of stroke and in 1984 for secondary prevention after myocardial infarction.
A history of efficacy
Aspirin also has a proven role in the secondary prevention of transient ischemic attack and ischemic stroke. Given early, it reduces the risk for a recurrent vascular event by 50% and long-term, compared with placebo, by 20%.
Interestingly, the doses are different in different areas of the world. In the United States, it’s either 81 mg or 325 mg. In Europe, it’s usually 100 mg. Until a few years ago, there was no single trial which used 100 mg of aspirin, compared with placebo for the secondary prevention of stroke.
If we look at dual antiplatelet therapy, the combination of aspirin and clopidogrel was not superior to aspirin alone or clopidogrel alone for long-term prevention, but the combination of dipyridamole and aspirin and the combination of cilostazol and aspirin were superior to aspirin alone for secondary stroke prevention. Short-term, within the first 30 days, the combination of aspirin and clopidogrel and the combination of ticagrelor and aspirin is superior to monotherapy but also have an increased risk for bleeding.
People with atrial fibrillation or embolic strokes need to be anticoagulated, but the addition of aspirin to anticoagulation does not increase efficacy, it only increases the risk for bleeding.
In people above the age of 75 years who have to take aspirin, there is an increased risk for upper gastrointestinal bleeding. These patients should, in addition, receive proton pump inhibitors.
The use of aspirin for the primary prevention of vascular events was promoted for almost 50 years all over the world, but in the last 5 years, a number of randomized trials clearly showed that aspirin is not effective, compared with placebo, in the primary prevention of vascular event stroke, myocardial infarction, and vascular death. It only increases the risk for bleeding.
So it’s a clear separation. Aspirin should not be used for primary prevention of vascular events, but it should be used in basically everyone who doesn’t have contraindications for secondary prevention of vascular events and vascular death.
Ladies and gentlemen, a drug that is 125 years old is also still one of the most used and affordable drugs all around the world. It’s highly effective and has only a small risk for major bleeding complications. It’s really time to celebrate aspirin for this achievement.
Dr. Diener is professor, department of neurology, Stroke Center-Headache Center, University Duisburg-Essen (Germany). A complete list of his financial disclosures is available at the link below.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Dear colleagues, I am Christoph Diener from the faculty of medicine at the University of Duisburg-Essen in Germany.
Usually in this video series, I report on interesting scientific studies in the field of neurology published in the last month. But I have to admit, June was a lousy month for new science in neurology. Therefore, this month I’d like to take a different approach and tell you about a very interesting, old drug.
We are celebrating the 125th anniversary of aspirin. Aspirin was first synthesized in Wuppertal, Germany, a city which is only 40 km from my location, by Felix Hoffmann. Hoffmann was searching for a new drug for his father who suffered from severe joint pain, and the available drugs at that time had terrible adverse events. This prompted him to work on a new drug, which was later called aspirin acetylsalicylic acid.
Aspirin has been used very successfully to the present day as therapy for joint pain or arthritis. But as you know, it’s also effective in headaches, in particular, tension-type headache. I think it’s one of the most used drugs in the world for the treatment of acute migraine attacks.
It’s also available in some European countries in intravenous form for the treatment of severe migraine attacks or in the emergency room, and it’s as effective as subcutaneous sumatriptan. It’s also an effective migraine preventive drug in a dose of 300 mg/d.
Discovering aspirin’s antiplatelet activity
There was an interesting observation by a dentist in the 1930s, who noted bleeding when he extracted teeth in people who took aspirin for joint pain. When he started to ask his patients about possible bleeding complications and vascular events, he observed that people who took aspirin didn’t have coronary myocardial infarctions.
It took a long time for people to discover that aspirin is not only a pain medication but also an antiplatelet agent. The first randomized study that showed that aspirin is effective in secondary prevention after myocardial infarction was published in 1974 in The New England Journal of Medicine. In 1980, aspirin was approved by the U.S. Food and Drug Administration for the secondary prevention of stroke and in 1984 for secondary prevention after myocardial infarction.
A history of efficacy
Aspirin also has a proven role in the secondary prevention of transient ischemic attack and ischemic stroke. Given early, it reduces the risk for a recurrent vascular event by 50% and long-term, compared with placebo, by 20%.
Interestingly, the doses are different in different areas of the world. In the United States, it’s either 81 mg or 325 mg. In Europe, it’s usually 100 mg. Until a few years ago, there was no single trial which used 100 mg of aspirin, compared with placebo for the secondary prevention of stroke.
If we look at dual antiplatelet therapy, the combination of aspirin and clopidogrel was not superior to aspirin alone or clopidogrel alone for long-term prevention, but the combination of dipyridamole and aspirin and the combination of cilostazol and aspirin were superior to aspirin alone for secondary stroke prevention. Short-term, within the first 30 days, the combination of aspirin and clopidogrel and the combination of ticagrelor and aspirin is superior to monotherapy but also have an increased risk for bleeding.
People with atrial fibrillation or embolic strokes need to be anticoagulated, but the addition of aspirin to anticoagulation does not increase efficacy, it only increases the risk for bleeding.
In people above the age of 75 years who have to take aspirin, there is an increased risk for upper gastrointestinal bleeding. These patients should, in addition, receive proton pump inhibitors.
The use of aspirin for the primary prevention of vascular events was promoted for almost 50 years all over the world, but in the last 5 years, a number of randomized trials clearly showed that aspirin is not effective, compared with placebo, in the primary prevention of vascular event stroke, myocardial infarction, and vascular death. It only increases the risk for bleeding.
So it’s a clear separation. Aspirin should not be used for primary prevention of vascular events, but it should be used in basically everyone who doesn’t have contraindications for secondary prevention of vascular events and vascular death.
Ladies and gentlemen, a drug that is 125 years old is also still one of the most used and affordable drugs all around the world. It’s highly effective and has only a small risk for major bleeding complications. It’s really time to celebrate aspirin for this achievement.
Dr. Diener is professor, department of neurology, Stroke Center-Headache Center, University Duisburg-Essen (Germany). A complete list of his financial disclosures is available at the link below.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Dear colleagues, I am Christoph Diener from the faculty of medicine at the University of Duisburg-Essen in Germany.
Usually in this video series, I report on interesting scientific studies in the field of neurology published in the last month. But I have to admit, June was a lousy month for new science in neurology. Therefore, this month I’d like to take a different approach and tell you about a very interesting, old drug.
We are celebrating the 125th anniversary of aspirin. Aspirin was first synthesized in Wuppertal, Germany, a city which is only 40 km from my location, by Felix Hoffmann. Hoffmann was searching for a new drug for his father who suffered from severe joint pain, and the available drugs at that time had terrible adverse events. This prompted him to work on a new drug, which was later called aspirin acetylsalicylic acid.
Aspirin has been used very successfully to the present day as therapy for joint pain or arthritis. But as you know, it’s also effective in headaches, in particular, tension-type headache. I think it’s one of the most used drugs in the world for the treatment of acute migraine attacks.
It’s also available in some European countries in intravenous form for the treatment of severe migraine attacks or in the emergency room, and it’s as effective as subcutaneous sumatriptan. It’s also an effective migraine preventive drug in a dose of 300 mg/d.
Discovering aspirin’s antiplatelet activity
There was an interesting observation by a dentist in the 1930s, who noted bleeding when he extracted teeth in people who took aspirin for joint pain. When he started to ask his patients about possible bleeding complications and vascular events, he observed that people who took aspirin didn’t have coronary myocardial infarctions.
It took a long time for people to discover that aspirin is not only a pain medication but also an antiplatelet agent. The first randomized study that showed that aspirin is effective in secondary prevention after myocardial infarction was published in 1974 in The New England Journal of Medicine. In 1980, aspirin was approved by the U.S. Food and Drug Administration for the secondary prevention of stroke and in 1984 for secondary prevention after myocardial infarction.
A history of efficacy
Aspirin also has a proven role in the secondary prevention of transient ischemic attack and ischemic stroke. Given early, it reduces the risk for a recurrent vascular event by 50% and long-term, compared with placebo, by 20%.
Interestingly, the doses are different in different areas of the world. In the United States, it’s either 81 mg or 325 mg. In Europe, it’s usually 100 mg. Until a few years ago, there was no single trial which used 100 mg of aspirin, compared with placebo for the secondary prevention of stroke.
If we look at dual antiplatelet therapy, the combination of aspirin and clopidogrel was not superior to aspirin alone or clopidogrel alone for long-term prevention, but the combination of dipyridamole and aspirin and the combination of cilostazol and aspirin were superior to aspirin alone for secondary stroke prevention. Short-term, within the first 30 days, the combination of aspirin and clopidogrel and the combination of ticagrelor and aspirin is superior to monotherapy but also have an increased risk for bleeding.
People with atrial fibrillation or embolic strokes need to be anticoagulated, but the addition of aspirin to anticoagulation does not increase efficacy, it only increases the risk for bleeding.
In people above the age of 75 years who have to take aspirin, there is an increased risk for upper gastrointestinal bleeding. These patients should, in addition, receive proton pump inhibitors.
The use of aspirin for the primary prevention of vascular events was promoted for almost 50 years all over the world, but in the last 5 years, a number of randomized trials clearly showed that aspirin is not effective, compared with placebo, in the primary prevention of vascular event stroke, myocardial infarction, and vascular death. It only increases the risk for bleeding.
So it’s a clear separation. Aspirin should not be used for primary prevention of vascular events, but it should be used in basically everyone who doesn’t have contraindications for secondary prevention of vascular events and vascular death.
Ladies and gentlemen, a drug that is 125 years old is also still one of the most used and affordable drugs all around the world. It’s highly effective and has only a small risk for major bleeding complications. It’s really time to celebrate aspirin for this achievement.
Dr. Diener is professor, department of neurology, Stroke Center-Headache Center, University Duisburg-Essen (Germany). A complete list of his financial disclosures is available at the link below.
A version of this article first appeared on Medscape.com.
Concerns that low LDL-C alters cognitive function challenged in novel analysis
PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.
The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).
For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.
Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.
Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
Mendelian randomization addresses complex issue
The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.
By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.
The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.
“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.
From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.
The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.
In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions
Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.
Data do not support low LDL-C as cognitive risk factor
Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.
“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”
In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.
“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.
Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.
PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.
The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).
For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.
Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.
Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
Mendelian randomization addresses complex issue
The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.
By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.
The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.
“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.
From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.
The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.
In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions
Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.
Data do not support low LDL-C as cognitive risk factor
Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.
“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”
In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.
“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.
Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.
PCSK9 inhibitors, which are among the most effective therapies for reducing LDL cholesterol (LDL-C), are associated with a neutral effect on cognitive function, according to a genetics-based Mendelian randomization study intended to sort out through the complexity of confounders.
The same study linked HMG-Co A reductase inhibitors (statins) with the potential for modest adverse neurocognitive effects, although these are likely to be outweighed by cardiovascular benefits, according to a collaborating team of investigators from the U.S. National Institutes of Health and the University of Oxford (England).
For clinicians and patients who continue to harbor concerns that cognitive function is threatened by very low LDL-C, this novel approach to evaluating risk is “reassuring,” according to the authors.
Early in clinical testing of PCSK9 inhibitors, a potential signal for adverse effects on cognitive function was reported but unconfirmed. This signal raised concern that extremely low levels of LDL-C, such as < 25 mg/dL, achieved with PCSK9 inhibitors might pose a risk to neurocognitive function.
Of several factors that provided a basis for concern, the PCSK9 enzyme is known to participate in brain development, according to the authors of this newly published study.
Mendelian randomization addresses complex issue
The objective of this Mendelian randomization analysis was to evaluate the relationship of PCSK9 inhibitors and statins on long-term neurocognitive function. Used previously to address other clinical issues, a drug-effect Mendelian randomization analysis evaluates genetic variants to determine whether there is a causal relationship between a risk, which in this case was lipid-lowering drugs, to a specific outcome, which was cognitive performance.
By looking directly at genetic variants that simulate the pharmacological inhibition of drug gene targets, the bias of confounders of clinical effects, such as baseline cognitive function, are avoided, according to the authors.
The message from this drug-effect Mendelian analysis was simple, according to the senior author of the study, Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics, National Institute of Alcohol Abuse and Alcoholism.
“Based on our data, we do not see a significant cognitive risk profile with PCSK9 inhibition associated with low LDL-C,” Dr. Lohoff said in an interview. He cautioned that “future long-term clinical studies are needed to confirm the absence of this effect,” but he and his coauthors noted that these data concur with the clinical studies.
From genome-wide association studies, single-nucleotide polymorphisms in PCSK9 and HMG-Co A reductase were extracted from a sample of more than 700,000 individuals of predominantly European ancestry. In the analysis, the investigators evaluated whether inhibition of PCSK9 or HMG-Co A reductase had an effect on seven clinical outcomes that relate to neurocognitive function, including memory, verbal intelligence, and reaction time, as well as biomarkers of cognitive function, such as cortical surface area.
The genetic effect of PCSK9 inhibition was “null for every cognitive-related outcome evaluated,” the investigators reported. The genetic effect of HMG-Co A reductase inhibition had a statistically significant but modest effect on cognitive performance (P = .03) and cortical surface area (P = .03). While the impact of HMG-Co A reductase inhibition on reaction time was stronger on a statistical basis (P = .0002), the investigators reported that it translated into a decrease of only 0.067 milliseconds per 38.7 mg/dL. They characterized this as a “small impact” unlikely to outweigh clinical benefits.
In an editorial that accompanied publication of this study, Brian A. Ference, MD, MPhil, provided context for the suitability of a Mendelian randomization analysis to address this or other questions regarding the impact of lipid-lowering therapies on clinical outcomes, and he ultimately concurred with the major conclusions
Ultimately, this analysis is consistent with other evidence that PCSK9 inhibition does not pose a risk of impaired cognitive function, he wrote. For statins, he concluded that this study “does not provide compelling evidence” to challenge their current clinical use.
Data do not support low LDL-C as cognitive risk factor
Moreover, this study – as well as other evidence – argues strongly against very low levels of LDL-C, regardless of how they are achieved, as a risk factor for diminished cognitive function, Dr. Ference, director of research in the division of translational therapeutics, University of Cambridge (England), said in an interview.
“There is no evidence from Mendelian randomization studies that lifelong exposure to lower LDL-C increases the risk of cognitive impairment,” he said. “This is true when evaluating lifelong exposure to lower LDL-C due to genetic variants in a wide variety of different genes or the genes that encode the target PCKS9 inhibitors, statins, or other lipid-lowering therapies.”
In other words, this study “adds to the accumulating evidence” that LDL-C lowering by itself does not contribute to an adverse impact on cognitive function despite persistent concern. This should not be surprising. Dr. Ference emphasized that there has never been strong evidence for an association.
“As I point out in the editorial, there is no biologically plausible mechanism by which reducing peripheral LDL-C should impact neurological function in any way, because the therapies do not cross the blood brain barrier, and because the nervous system produces its own cholesterol to maintain the integrity of membranes in nervous system cells,” he explained.
Dr. Lohoff reports no potential conflicts of interest. Dr. Ference has financial relationships with numerous pharmaceutical companies including those that make lipid-lowering therapies.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
A ‘promising target’ to improve outcomes in late-life depression
A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.
Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.
Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.
“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.
The study was published online in JAMA Network Open.
A leading cause of disability
LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.
Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.
Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.
An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.
The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”
Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”
“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.
The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.
They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.
They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
Emerging model
The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.
The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.
They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”
Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.
Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).
They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).
Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).
Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.
Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).
In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.
The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).
“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.
“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.
One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”
The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”
Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.
Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.
Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.
“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.
The study was published online in JAMA Network Open.
A leading cause of disability
LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.
Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.
Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.
An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.
The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”
Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”
“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.
The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.
They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.
They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
Emerging model
The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.
The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.
They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”
Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.
Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).
They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).
Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).
Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.
Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).
In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.
The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).
“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.
“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.
One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”
The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”
Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.
Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.
Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.
“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.
The study was published online in JAMA Network Open.
A leading cause of disability
LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.
Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.
Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.
An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.
The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”
Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”
“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.
The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.
They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.
They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
Emerging model
The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.
The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.
They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”
Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.
Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).
They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).
Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).
Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.
Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).
In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.
The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).
“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.
“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.
One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”
The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”
Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
AAP updates hyperbilirubinemia guideline
Raising phototherapy thresholds and revising risk assessment are among the key changes in the American Academy of Pediatrics’ updated guidelines for managing hyperbilirubinemia in infants 35 weeks’ gestation and older.
“More than 80% of newborn infants will have some degree of jaundice,” Alex R. Kemper, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and coauthors wrote. Careful monitoring is needed manage high bilirubin concentrations and avoid acute bilirubin encephalopathy (ABE) and kernicterus, a disabling neurologic condition.
The current revision, published in Pediatrics, updates and replaces the 2004 AAP clinical practice guidelines for the management and prevention of hyperbilirubinemia in newborns of at least 35 weeks’ gestation.
The guideline committee reviewed evidence published since the previous guidelines were issued in 2004, and addressed similar issues of prevention, risk assessment, monitoring, and treatment.
A notable change from 2004 was the inclusion of a 2009 recommendation update for “universal predischarge bilirubin screening with measures of total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) linked to specific recommendations for follow-up,” the authors wrote.
In terms of prevention, recommendations include a direct antiglobulin test (DAT) for infants whose mother’s antibody screen was positive or unknown. In addition, exclusive breastfeeding is known to be associated with hyperbilirubinemia, but clinicians should support breastfeeding while monitoring for signs of hyperbilirubinemia because of suboptimal feeding, the authors noted. However, the guidelines recommend against oral supplementation with water or dextrose water to prevent hyperbilirubinemia.
For assessment and monitoring, the guidelines advise the use of total serum bilirubin (TSB) as the definitive test for hyperbilirubinemia to guide phototherapy and escalation of care, including exchange transfusion. “The presence of hyperbilirubinemia neurotoxicity risk factors lowers the threshold for treatment with phototherapy and the level at which care should be escalated,” the authors wrote. They also emphasized the need to consider glucose-6-phosphate dehydrogenase deficiency, a genetic condition that decreases protection against oxidative stress and has been identified as a leading cause of hazardous hyperbilirubinemia worldwide.
The guidelines recommend assessing all infants for jaundice at least every 12 hours after delivery until discharge, with TSB or TcB measured as soon as possible for those with suspected jaundice. The complete guidelines include charts for TSB levels to guide escalation of care. “Blood for TSB can be obtained at the time it is collected for newborn screening tests to avoid an additional heel stick,” the authors noted.
The rate of increase in TSB or TcB, if more than one measure is available, may identify infants at higher risk of hyperbilirubinemia, according to the guidelines, and a possible delay of hospital discharge may be needed for infants if appropriate follow-up is not feasible.
In terms of treatment, new evidence that bilirubin neurotoxicity does not occur until concentrations well above those given in the 2004 guidelines justified raising the treatment thresholds, although by a narrow range. “With the increased phototherapy thresholds, appropriately following the current guidelines including bilirubin screening during the birth hospitalization and timely postdischarge follow-up is important,” the authors wrote. The new thresholds, outlined in the complete guidelines, are based on gestational age, hyperbilirubinemia neurotoxicity risk factors, and the age of the infant in hours. However, infants may be treated at lower levels, based on individual circumstances, family preferences, and shared decision-making with clinicians. Home-based phototherapy may be used in some infants, but should not be used if there is a question about the device quality, delivery time, and ability of caregivers to use the device correctly.
“Discontinuing phototherapy is an option when the TSB has decreased by at least 2 mg/dL below the hour-specific threshold at the initiation of phototherapy,” and follow-up should be based on risk of rebound hyperbilirubinemia, according to the guidelines.
“This clinical practice guideline provides indications and approaches for phototherapy and escalation of care and when treatment and monitoring can be safely discontinued,” However, clinicians should understand the rationale for the recommendations and combine them with their clinical judgment, including shared decision-making when appropriate, the authors concluded.
Updated evidence supports escalating care
The take-home message for pediatricians is that neonatal hyperbilirubinemia is a very common finding, and complications are rare, but the condition can result in devastating life-long results, Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“Previous guidelines published in 2004 and updated in 2009 included evidence-based recommendations, but additional research was still needed to provide guidance for providers to prevent complications of hyperbilirubinemia,” said Dr. Haut, who was not involved in producing the guidelines.
“New data documenting additional risk factors, the importance of ongoing breastfeeding support, and addressing hyperbilirubinemia as an urgent problem” are additions to prevention methods in the latest published guidelines, she said.
“Acute encephalopathy and kernicterus can result from hyperbilirubinemia with severe and devastating neurologic effects, but are preventable by early identification and treatment,” said Dr. Haut. Therefore, “it is not surprising that the AAP utilized continuing and more recent evidence to support new recommendations. Both maternal and neonatal risk factors have long been considered in the development of neonatal hyperbilirubinemia, but recent recommendations incorporate additional risk factor evaluation and urgency in time to appropriate care. Detailed thresholds for phototherapy and exchange transfusion will benefit the families of full-term infants without other risk factors and escalate care for those neonates with risk factors.”
However, potential barriers to following the guidelines persist, Dr. Haut noted.
“Frequent infant follow-up can be challenging for busy primary care offices with outpatient laboratory results often taking much longer to obtain than in a hospital setting,” she said.
Also, “taking a newborn to the emergency department or an inpatient laboratory can be frightening for families with the risk of illness exposure. Frequent monitoring of serum bilirubin levels is disturbing for parents and inconvenient immediately postpartum,” Dr. Haut explained. “Few practices utilize transcutaneous bilirubin monitoring which may be one method of added screening.”
In addition, “despite the importance of breastfeeding, ongoing support is not readily available for mothers after hospital discharge. A lactation specialist in the office setting can take the burden off providers and add opportunity for family education.”
As for additional research, “continued evaluation of the comparison of transcutaneous bilirubin monitoring and serum levels along with the use of transcutaneous monitoring in facilities outside the hospital setting may be warranted,” Dr. Haut said. “Data collection on incidence and accompanying risk factors of neonates who develop acute hyperbilirubinemia encephalopathy and kernicterus is a long-term study opportunity.”
The guidelines received no external funding. Lead author Dr. Kemper had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
Raising phototherapy thresholds and revising risk assessment are among the key changes in the American Academy of Pediatrics’ updated guidelines for managing hyperbilirubinemia in infants 35 weeks’ gestation and older.
“More than 80% of newborn infants will have some degree of jaundice,” Alex R. Kemper, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and coauthors wrote. Careful monitoring is needed manage high bilirubin concentrations and avoid acute bilirubin encephalopathy (ABE) and kernicterus, a disabling neurologic condition.
The current revision, published in Pediatrics, updates and replaces the 2004 AAP clinical practice guidelines for the management and prevention of hyperbilirubinemia in newborns of at least 35 weeks’ gestation.
The guideline committee reviewed evidence published since the previous guidelines were issued in 2004, and addressed similar issues of prevention, risk assessment, monitoring, and treatment.
A notable change from 2004 was the inclusion of a 2009 recommendation update for “universal predischarge bilirubin screening with measures of total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) linked to specific recommendations for follow-up,” the authors wrote.
In terms of prevention, recommendations include a direct antiglobulin test (DAT) for infants whose mother’s antibody screen was positive or unknown. In addition, exclusive breastfeeding is known to be associated with hyperbilirubinemia, but clinicians should support breastfeeding while monitoring for signs of hyperbilirubinemia because of suboptimal feeding, the authors noted. However, the guidelines recommend against oral supplementation with water or dextrose water to prevent hyperbilirubinemia.
For assessment and monitoring, the guidelines advise the use of total serum bilirubin (TSB) as the definitive test for hyperbilirubinemia to guide phototherapy and escalation of care, including exchange transfusion. “The presence of hyperbilirubinemia neurotoxicity risk factors lowers the threshold for treatment with phototherapy and the level at which care should be escalated,” the authors wrote. They also emphasized the need to consider glucose-6-phosphate dehydrogenase deficiency, a genetic condition that decreases protection against oxidative stress and has been identified as a leading cause of hazardous hyperbilirubinemia worldwide.
The guidelines recommend assessing all infants for jaundice at least every 12 hours after delivery until discharge, with TSB or TcB measured as soon as possible for those with suspected jaundice. The complete guidelines include charts for TSB levels to guide escalation of care. “Blood for TSB can be obtained at the time it is collected for newborn screening tests to avoid an additional heel stick,” the authors noted.
The rate of increase in TSB or TcB, if more than one measure is available, may identify infants at higher risk of hyperbilirubinemia, according to the guidelines, and a possible delay of hospital discharge may be needed for infants if appropriate follow-up is not feasible.
In terms of treatment, new evidence that bilirubin neurotoxicity does not occur until concentrations well above those given in the 2004 guidelines justified raising the treatment thresholds, although by a narrow range. “With the increased phototherapy thresholds, appropriately following the current guidelines including bilirubin screening during the birth hospitalization and timely postdischarge follow-up is important,” the authors wrote. The new thresholds, outlined in the complete guidelines, are based on gestational age, hyperbilirubinemia neurotoxicity risk factors, and the age of the infant in hours. However, infants may be treated at lower levels, based on individual circumstances, family preferences, and shared decision-making with clinicians. Home-based phototherapy may be used in some infants, but should not be used if there is a question about the device quality, delivery time, and ability of caregivers to use the device correctly.
“Discontinuing phototherapy is an option when the TSB has decreased by at least 2 mg/dL below the hour-specific threshold at the initiation of phototherapy,” and follow-up should be based on risk of rebound hyperbilirubinemia, according to the guidelines.
“This clinical practice guideline provides indications and approaches for phototherapy and escalation of care and when treatment and monitoring can be safely discontinued,” However, clinicians should understand the rationale for the recommendations and combine them with their clinical judgment, including shared decision-making when appropriate, the authors concluded.
Updated evidence supports escalating care
The take-home message for pediatricians is that neonatal hyperbilirubinemia is a very common finding, and complications are rare, but the condition can result in devastating life-long results, Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“Previous guidelines published in 2004 and updated in 2009 included evidence-based recommendations, but additional research was still needed to provide guidance for providers to prevent complications of hyperbilirubinemia,” said Dr. Haut, who was not involved in producing the guidelines.
“New data documenting additional risk factors, the importance of ongoing breastfeeding support, and addressing hyperbilirubinemia as an urgent problem” are additions to prevention methods in the latest published guidelines, she said.
“Acute encephalopathy and kernicterus can result from hyperbilirubinemia with severe and devastating neurologic effects, but are preventable by early identification and treatment,” said Dr. Haut. Therefore, “it is not surprising that the AAP utilized continuing and more recent evidence to support new recommendations. Both maternal and neonatal risk factors have long been considered in the development of neonatal hyperbilirubinemia, but recent recommendations incorporate additional risk factor evaluation and urgency in time to appropriate care. Detailed thresholds for phototherapy and exchange transfusion will benefit the families of full-term infants without other risk factors and escalate care for those neonates with risk factors.”
However, potential barriers to following the guidelines persist, Dr. Haut noted.
“Frequent infant follow-up can be challenging for busy primary care offices with outpatient laboratory results often taking much longer to obtain than in a hospital setting,” she said.
Also, “taking a newborn to the emergency department or an inpatient laboratory can be frightening for families with the risk of illness exposure. Frequent monitoring of serum bilirubin levels is disturbing for parents and inconvenient immediately postpartum,” Dr. Haut explained. “Few practices utilize transcutaneous bilirubin monitoring which may be one method of added screening.”
In addition, “despite the importance of breastfeeding, ongoing support is not readily available for mothers after hospital discharge. A lactation specialist in the office setting can take the burden off providers and add opportunity for family education.”
As for additional research, “continued evaluation of the comparison of transcutaneous bilirubin monitoring and serum levels along with the use of transcutaneous monitoring in facilities outside the hospital setting may be warranted,” Dr. Haut said. “Data collection on incidence and accompanying risk factors of neonates who develop acute hyperbilirubinemia encephalopathy and kernicterus is a long-term study opportunity.”
The guidelines received no external funding. Lead author Dr. Kemper had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
Raising phototherapy thresholds and revising risk assessment are among the key changes in the American Academy of Pediatrics’ updated guidelines for managing hyperbilirubinemia in infants 35 weeks’ gestation and older.
“More than 80% of newborn infants will have some degree of jaundice,” Alex R. Kemper, MD, of Nationwide Children’s Hospital, Columbus, Ohio, and coauthors wrote. Careful monitoring is needed manage high bilirubin concentrations and avoid acute bilirubin encephalopathy (ABE) and kernicterus, a disabling neurologic condition.
The current revision, published in Pediatrics, updates and replaces the 2004 AAP clinical practice guidelines for the management and prevention of hyperbilirubinemia in newborns of at least 35 weeks’ gestation.
The guideline committee reviewed evidence published since the previous guidelines were issued in 2004, and addressed similar issues of prevention, risk assessment, monitoring, and treatment.
A notable change from 2004 was the inclusion of a 2009 recommendation update for “universal predischarge bilirubin screening with measures of total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) linked to specific recommendations for follow-up,” the authors wrote.
In terms of prevention, recommendations include a direct antiglobulin test (DAT) for infants whose mother’s antibody screen was positive or unknown. In addition, exclusive breastfeeding is known to be associated with hyperbilirubinemia, but clinicians should support breastfeeding while monitoring for signs of hyperbilirubinemia because of suboptimal feeding, the authors noted. However, the guidelines recommend against oral supplementation with water or dextrose water to prevent hyperbilirubinemia.
For assessment and monitoring, the guidelines advise the use of total serum bilirubin (TSB) as the definitive test for hyperbilirubinemia to guide phototherapy and escalation of care, including exchange transfusion. “The presence of hyperbilirubinemia neurotoxicity risk factors lowers the threshold for treatment with phototherapy and the level at which care should be escalated,” the authors wrote. They also emphasized the need to consider glucose-6-phosphate dehydrogenase deficiency, a genetic condition that decreases protection against oxidative stress and has been identified as a leading cause of hazardous hyperbilirubinemia worldwide.
The guidelines recommend assessing all infants for jaundice at least every 12 hours after delivery until discharge, with TSB or TcB measured as soon as possible for those with suspected jaundice. The complete guidelines include charts for TSB levels to guide escalation of care. “Blood for TSB can be obtained at the time it is collected for newborn screening tests to avoid an additional heel stick,” the authors noted.
The rate of increase in TSB or TcB, if more than one measure is available, may identify infants at higher risk of hyperbilirubinemia, according to the guidelines, and a possible delay of hospital discharge may be needed for infants if appropriate follow-up is not feasible.
In terms of treatment, new evidence that bilirubin neurotoxicity does not occur until concentrations well above those given in the 2004 guidelines justified raising the treatment thresholds, although by a narrow range. “With the increased phototherapy thresholds, appropriately following the current guidelines including bilirubin screening during the birth hospitalization and timely postdischarge follow-up is important,” the authors wrote. The new thresholds, outlined in the complete guidelines, are based on gestational age, hyperbilirubinemia neurotoxicity risk factors, and the age of the infant in hours. However, infants may be treated at lower levels, based on individual circumstances, family preferences, and shared decision-making with clinicians. Home-based phototherapy may be used in some infants, but should not be used if there is a question about the device quality, delivery time, and ability of caregivers to use the device correctly.
“Discontinuing phototherapy is an option when the TSB has decreased by at least 2 mg/dL below the hour-specific threshold at the initiation of phototherapy,” and follow-up should be based on risk of rebound hyperbilirubinemia, according to the guidelines.
“This clinical practice guideline provides indications and approaches for phototherapy and escalation of care and when treatment and monitoring can be safely discontinued,” However, clinicians should understand the rationale for the recommendations and combine them with their clinical judgment, including shared decision-making when appropriate, the authors concluded.
Updated evidence supports escalating care
The take-home message for pediatricians is that neonatal hyperbilirubinemia is a very common finding, and complications are rare, but the condition can result in devastating life-long results, Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“Previous guidelines published in 2004 and updated in 2009 included evidence-based recommendations, but additional research was still needed to provide guidance for providers to prevent complications of hyperbilirubinemia,” said Dr. Haut, who was not involved in producing the guidelines.
“New data documenting additional risk factors, the importance of ongoing breastfeeding support, and addressing hyperbilirubinemia as an urgent problem” are additions to prevention methods in the latest published guidelines, she said.
“Acute encephalopathy and kernicterus can result from hyperbilirubinemia with severe and devastating neurologic effects, but are preventable by early identification and treatment,” said Dr. Haut. Therefore, “it is not surprising that the AAP utilized continuing and more recent evidence to support new recommendations. Both maternal and neonatal risk factors have long been considered in the development of neonatal hyperbilirubinemia, but recent recommendations incorporate additional risk factor evaluation and urgency in time to appropriate care. Detailed thresholds for phototherapy and exchange transfusion will benefit the families of full-term infants without other risk factors and escalate care for those neonates with risk factors.”
However, potential barriers to following the guidelines persist, Dr. Haut noted.
“Frequent infant follow-up can be challenging for busy primary care offices with outpatient laboratory results often taking much longer to obtain than in a hospital setting,” she said.
Also, “taking a newborn to the emergency department or an inpatient laboratory can be frightening for families with the risk of illness exposure. Frequent monitoring of serum bilirubin levels is disturbing for parents and inconvenient immediately postpartum,” Dr. Haut explained. “Few practices utilize transcutaneous bilirubin monitoring which may be one method of added screening.”
In addition, “despite the importance of breastfeeding, ongoing support is not readily available for mothers after hospital discharge. A lactation specialist in the office setting can take the burden off providers and add opportunity for family education.”
As for additional research, “continued evaluation of the comparison of transcutaneous bilirubin monitoring and serum levels along with the use of transcutaneous monitoring in facilities outside the hospital setting may be warranted,” Dr. Haut said. “Data collection on incidence and accompanying risk factors of neonates who develop acute hyperbilirubinemia encephalopathy and kernicterus is a long-term study opportunity.”
The guidelines received no external funding. Lead author Dr. Kemper had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose and serves on the editorial advisory board of Pediatric News.
FROM PEDIATRICS
Regular exercise appears to slow cognitive decline in MCI
(MCI), new research from the largest study of its kind suggests. Topline results from the EXERT trial showed patients with MCI who participated regularly in either aerobic exercise or stretching/balance/range-of-motion exercises maintained stable global cognitive function over 12 months of follow-up – with no differences between the two types of exercise.
“We’re excited about these findings, because these types of exercises that we’re seeing can protect against cognitive decline are accessible to everyone and therefore scalable to the public,” study investigator Laura Baker, PhD, Wake Forest University School of Medicine, Winston-Salem, N.C., said at a press briefing.
The topline results were presented at the 2022 Alzheimer’s Association International Conference.
No decline
The 18-month EXERT trial was designed to be the definitive study to answer the question about whether exercise can slow cognitive decline in older adults with amnestic MCI, Dr. Baker reported. Investigators enrolled 296 sedentary men and women with MCI (mean age, about 75 years). All were randomly allocated to either an aerobic exercise group (maintaining a heart rate at about 70%-85%) or a stretching and balance group (maintaining heart rate less than 35%).
Both groups exercised four times per week for about 30-40 minutes. In the first 12 months they were supervised by a trainer at the YMCA and then they exercised independently for the final 6 months.
Participants were assessed at baseline and every 6 months. The primary endpoint was change from baseline on the ADAS-Cog-Exec, a validated measure of global cognitive function, at the end of the 12 months of supervised exercise.
During the first 12 months, participants completed over 31,000 sessions of exercise, which is “quite impressive,” Dr. Baker said.
Over the first 12 months, neither the aerobic group nor the stretch/balance group showed a decline on the ADAS-Cog-Exec.
“We saw no group differences, and importantly, no decline after 12 months,” Dr. Baker reported.
Supported exercise is ‘crucial’
To help “make sense” of these findings, Dr. Baker noted that 12-month changes in the ADAS-Cog-Exec for the EXERT intervention groups were also compared with a “usual care” cohort of adults matched for age, sex, education, baseline cognitive status, and APOE4 genotype.
In this “apples-to-apples” comparison, the usual care cohort showed the expected decline or worsening of cognitive function over 12 months on the ADAS-Cog-Exec, but the EXERT exercise groups did not.
Dr. Baker noted that both exercise groups received equal amounts of weekly socialization, which may have contributed to the apparent protective effects on the brain.
A greater volume of exercise in EXERT, compared with other trials, may also be a factor. Each individual participant in EXERT completed more than 100 hours of exercise.
“The take-home message is that an increased amount of either low-intensity or high-intensity exercise for 120-150 minutes per week for 12 months may slow cognitive decline in sedentary older adults with MCI,” Dr. Baker said.
“What’s critical is that this regular exercise must be supported in these older [patients] with MCI. It must be supervised. There has to be some social component,” she added.
In her view, 120 minutes of regular supported exercise for sedentary individuals with MCI “needs to be part of the recommendation for risk reduction.”
Important study
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that several studies over the years have suggested that different types of exercise can have benefits on the brain.
“What’s important about this study is that it’s in a population of people that have MCI and are already experiencing memory changes,” Dr. Snyder said.
“The results suggest that engaging in both of these types of exercise may be beneficial for our brain. And given that this is the largest study of its kind in a population of people with MCI, it suggests it’s ‘never too late’ to start exercising,” she added.
Dr. Snyder noted the importance of continuing this work and to continue following these individuals “over time as well.”
The study was funded by the National Institutes of Health, National Institute on Aging. Dr. Baker and Dr. Snyder have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MCI), new research from the largest study of its kind suggests. Topline results from the EXERT trial showed patients with MCI who participated regularly in either aerobic exercise or stretching/balance/range-of-motion exercises maintained stable global cognitive function over 12 months of follow-up – with no differences between the two types of exercise.
“We’re excited about these findings, because these types of exercises that we’re seeing can protect against cognitive decline are accessible to everyone and therefore scalable to the public,” study investigator Laura Baker, PhD, Wake Forest University School of Medicine, Winston-Salem, N.C., said at a press briefing.
The topline results were presented at the 2022 Alzheimer’s Association International Conference.
No decline
The 18-month EXERT trial was designed to be the definitive study to answer the question about whether exercise can slow cognitive decline in older adults with amnestic MCI, Dr. Baker reported. Investigators enrolled 296 sedentary men and women with MCI (mean age, about 75 years). All were randomly allocated to either an aerobic exercise group (maintaining a heart rate at about 70%-85%) or a stretching and balance group (maintaining heart rate less than 35%).
Both groups exercised four times per week for about 30-40 minutes. In the first 12 months they were supervised by a trainer at the YMCA and then they exercised independently for the final 6 months.
Participants were assessed at baseline and every 6 months. The primary endpoint was change from baseline on the ADAS-Cog-Exec, a validated measure of global cognitive function, at the end of the 12 months of supervised exercise.
During the first 12 months, participants completed over 31,000 sessions of exercise, which is “quite impressive,” Dr. Baker said.
Over the first 12 months, neither the aerobic group nor the stretch/balance group showed a decline on the ADAS-Cog-Exec.
“We saw no group differences, and importantly, no decline after 12 months,” Dr. Baker reported.
Supported exercise is ‘crucial’
To help “make sense” of these findings, Dr. Baker noted that 12-month changes in the ADAS-Cog-Exec for the EXERT intervention groups were also compared with a “usual care” cohort of adults matched for age, sex, education, baseline cognitive status, and APOE4 genotype.
In this “apples-to-apples” comparison, the usual care cohort showed the expected decline or worsening of cognitive function over 12 months on the ADAS-Cog-Exec, but the EXERT exercise groups did not.
Dr. Baker noted that both exercise groups received equal amounts of weekly socialization, which may have contributed to the apparent protective effects on the brain.
A greater volume of exercise in EXERT, compared with other trials, may also be a factor. Each individual participant in EXERT completed more than 100 hours of exercise.
“The take-home message is that an increased amount of either low-intensity or high-intensity exercise for 120-150 minutes per week for 12 months may slow cognitive decline in sedentary older adults with MCI,” Dr. Baker said.
“What’s critical is that this regular exercise must be supported in these older [patients] with MCI. It must be supervised. There has to be some social component,” she added.
In her view, 120 minutes of regular supported exercise for sedentary individuals with MCI “needs to be part of the recommendation for risk reduction.”
Important study
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that several studies over the years have suggested that different types of exercise can have benefits on the brain.
“What’s important about this study is that it’s in a population of people that have MCI and are already experiencing memory changes,” Dr. Snyder said.
“The results suggest that engaging in both of these types of exercise may be beneficial for our brain. And given that this is the largest study of its kind in a population of people with MCI, it suggests it’s ‘never too late’ to start exercising,” she added.
Dr. Snyder noted the importance of continuing this work and to continue following these individuals “over time as well.”
The study was funded by the National Institutes of Health, National Institute on Aging. Dr. Baker and Dr. Snyder have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MCI), new research from the largest study of its kind suggests. Topline results from the EXERT trial showed patients with MCI who participated regularly in either aerobic exercise or stretching/balance/range-of-motion exercises maintained stable global cognitive function over 12 months of follow-up – with no differences between the two types of exercise.
“We’re excited about these findings, because these types of exercises that we’re seeing can protect against cognitive decline are accessible to everyone and therefore scalable to the public,” study investigator Laura Baker, PhD, Wake Forest University School of Medicine, Winston-Salem, N.C., said at a press briefing.
The topline results were presented at the 2022 Alzheimer’s Association International Conference.
No decline
The 18-month EXERT trial was designed to be the definitive study to answer the question about whether exercise can slow cognitive decline in older adults with amnestic MCI, Dr. Baker reported. Investigators enrolled 296 sedentary men and women with MCI (mean age, about 75 years). All were randomly allocated to either an aerobic exercise group (maintaining a heart rate at about 70%-85%) or a stretching and balance group (maintaining heart rate less than 35%).
Both groups exercised four times per week for about 30-40 minutes. In the first 12 months they were supervised by a trainer at the YMCA and then they exercised independently for the final 6 months.
Participants were assessed at baseline and every 6 months. The primary endpoint was change from baseline on the ADAS-Cog-Exec, a validated measure of global cognitive function, at the end of the 12 months of supervised exercise.
During the first 12 months, participants completed over 31,000 sessions of exercise, which is “quite impressive,” Dr. Baker said.
Over the first 12 months, neither the aerobic group nor the stretch/balance group showed a decline on the ADAS-Cog-Exec.
“We saw no group differences, and importantly, no decline after 12 months,” Dr. Baker reported.
Supported exercise is ‘crucial’
To help “make sense” of these findings, Dr. Baker noted that 12-month changes in the ADAS-Cog-Exec for the EXERT intervention groups were also compared with a “usual care” cohort of adults matched for age, sex, education, baseline cognitive status, and APOE4 genotype.
In this “apples-to-apples” comparison, the usual care cohort showed the expected decline or worsening of cognitive function over 12 months on the ADAS-Cog-Exec, but the EXERT exercise groups did not.
Dr. Baker noted that both exercise groups received equal amounts of weekly socialization, which may have contributed to the apparent protective effects on the brain.
A greater volume of exercise in EXERT, compared with other trials, may also be a factor. Each individual participant in EXERT completed more than 100 hours of exercise.
“The take-home message is that an increased amount of either low-intensity or high-intensity exercise for 120-150 minutes per week for 12 months may slow cognitive decline in sedentary older adults with MCI,” Dr. Baker said.
“What’s critical is that this regular exercise must be supported in these older [patients] with MCI. It must be supervised. There has to be some social component,” she added.
In her view, 120 minutes of regular supported exercise for sedentary individuals with MCI “needs to be part of the recommendation for risk reduction.”
Important study
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that several studies over the years have suggested that different types of exercise can have benefits on the brain.
“What’s important about this study is that it’s in a population of people that have MCI and are already experiencing memory changes,” Dr. Snyder said.
“The results suggest that engaging in both of these types of exercise may be beneficial for our brain. And given that this is the largest study of its kind in a population of people with MCI, it suggests it’s ‘never too late’ to start exercising,” she added.
Dr. Snyder noted the importance of continuing this work and to continue following these individuals “over time as well.”
The study was funded by the National Institutes of Health, National Institute on Aging. Dr. Baker and Dr. Snyder have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From AAIC 2022
Waking up at night could be your brain boosting your memory
We tend to think a good night’s sleep should be uninterrupted, but surprising new research from the University of Copenhagen suggests just the opposite:
The study, done on mice, found that the stress transmitter noradrenaline wakes up the brain many times a night. These “microarousals” were linked to memory consolidation, meaning they help you remember the previous day’s events. In fact, the more “awake” you are during a microarousal, the better the memory boost, suggests the research, which was published in Nature Neuroscience.
“Every time I wake up in the middle of the night now, I think – ah, nice, I probably just had great memory-boosting sleep,” said study author Celia Kjaerby, PhD, an assistant professor at the university’s Center for Translational Neuromedicine.
The findings add insight to what happens in the brain during sleep and may help pave the way for new treatments for those who have sleep disorders.
Waves of noradrenaline
Previous research has suggested that noradrenaline – a hormone that increases during stress but also helps you stay focused – is inactive during sleep. So, the researchers were surprised to see high levels of it in the brains of the sleeping rodents.
“I still remember seeing the first traces showing the brain activity of the norepinephrine stress system during sleep. We could not believe our eyes,” Dr. Kjaerby said. “Everyone had thought the system would be quiet. And now we have found out that it completely controls the microarchitecture of sleep.”
Those noradrenaline levels rise and fall like waves every 30 seconds during non-REM (NREM) sleep. At each “peak” the brain is briefly awake, and at each “valley” it is asleep. Typically, these awakenings are so brief that the sleeping subject does not notice. But the higher the rise, the longer the awakening – and the more likely the sleeper may notice.
During the valleys, or when norepinephrine drops, so-called sleep spindles occur.
“These are short oscillatory bursts of brain activity linked to memory consolidation,” Dr. Kjaerby said. Occasionally there is a “deep valley,” lasting 3-5 minutes, leading to more sleep spindles. The mice with the most deep valleys also had the best memories, the researchers noted.
“We have shown that the amount of these super-boosts of sleep spindles, and not REM sleep, defines how well you remember the experiences you had prior to going to sleep,” said Dr. Kjaerby.
Deep valleys were followed by longer awakenings, the researchers observed. So, the longer the valley, the longer the awakening – and the better the memory boost. This means that, though restless sleep is not good, waking up briefly may be a natural part of memory-related sleep phases and may even mean you’ve slept well.
What happens in our brains when we sleep: Piecing it together
The findings fit with previous clinical data that shows we wake up roughly 100-plus times a night, mostly during NREM sleep stage 2 (the spindle-rich sleep stage), Dr. Kjaerby said.
Still, more research on these small awakenings is needed, Dr. Kjaerby said, noting that professor Maiken Nedergaard, MD, another author of this study, has found that the brain cleans up waste products through a rinsing fluid system.
“It remains a puzzle why the fluid system is so active when we sleep,” Dr. Kjaerby said. “We believe these short awakenings could potentially be the key to answering this question.”
A version of this article first appeared on WebMD.com.
We tend to think a good night’s sleep should be uninterrupted, but surprising new research from the University of Copenhagen suggests just the opposite:
The study, done on mice, found that the stress transmitter noradrenaline wakes up the brain many times a night. These “microarousals” were linked to memory consolidation, meaning they help you remember the previous day’s events. In fact, the more “awake” you are during a microarousal, the better the memory boost, suggests the research, which was published in Nature Neuroscience.
“Every time I wake up in the middle of the night now, I think – ah, nice, I probably just had great memory-boosting sleep,” said study author Celia Kjaerby, PhD, an assistant professor at the university’s Center for Translational Neuromedicine.
The findings add insight to what happens in the brain during sleep and may help pave the way for new treatments for those who have sleep disorders.
Waves of noradrenaline
Previous research has suggested that noradrenaline – a hormone that increases during stress but also helps you stay focused – is inactive during sleep. So, the researchers were surprised to see high levels of it in the brains of the sleeping rodents.
“I still remember seeing the first traces showing the brain activity of the norepinephrine stress system during sleep. We could not believe our eyes,” Dr. Kjaerby said. “Everyone had thought the system would be quiet. And now we have found out that it completely controls the microarchitecture of sleep.”
Those noradrenaline levels rise and fall like waves every 30 seconds during non-REM (NREM) sleep. At each “peak” the brain is briefly awake, and at each “valley” it is asleep. Typically, these awakenings are so brief that the sleeping subject does not notice. But the higher the rise, the longer the awakening – and the more likely the sleeper may notice.
During the valleys, or when norepinephrine drops, so-called sleep spindles occur.
“These are short oscillatory bursts of brain activity linked to memory consolidation,” Dr. Kjaerby said. Occasionally there is a “deep valley,” lasting 3-5 minutes, leading to more sleep spindles. The mice with the most deep valleys also had the best memories, the researchers noted.
“We have shown that the amount of these super-boosts of sleep spindles, and not REM sleep, defines how well you remember the experiences you had prior to going to sleep,” said Dr. Kjaerby.
Deep valleys were followed by longer awakenings, the researchers observed. So, the longer the valley, the longer the awakening – and the better the memory boost. This means that, though restless sleep is not good, waking up briefly may be a natural part of memory-related sleep phases and may even mean you’ve slept well.
What happens in our brains when we sleep: Piecing it together
The findings fit with previous clinical data that shows we wake up roughly 100-plus times a night, mostly during NREM sleep stage 2 (the spindle-rich sleep stage), Dr. Kjaerby said.
Still, more research on these small awakenings is needed, Dr. Kjaerby said, noting that professor Maiken Nedergaard, MD, another author of this study, has found that the brain cleans up waste products through a rinsing fluid system.
“It remains a puzzle why the fluid system is so active when we sleep,” Dr. Kjaerby said. “We believe these short awakenings could potentially be the key to answering this question.”
A version of this article first appeared on WebMD.com.
We tend to think a good night’s sleep should be uninterrupted, but surprising new research from the University of Copenhagen suggests just the opposite:
The study, done on mice, found that the stress transmitter noradrenaline wakes up the brain many times a night. These “microarousals” were linked to memory consolidation, meaning they help you remember the previous day’s events. In fact, the more “awake” you are during a microarousal, the better the memory boost, suggests the research, which was published in Nature Neuroscience.
“Every time I wake up in the middle of the night now, I think – ah, nice, I probably just had great memory-boosting sleep,” said study author Celia Kjaerby, PhD, an assistant professor at the university’s Center for Translational Neuromedicine.
The findings add insight to what happens in the brain during sleep and may help pave the way for new treatments for those who have sleep disorders.
Waves of noradrenaline
Previous research has suggested that noradrenaline – a hormone that increases during stress but also helps you stay focused – is inactive during sleep. So, the researchers were surprised to see high levels of it in the brains of the sleeping rodents.
“I still remember seeing the first traces showing the brain activity of the norepinephrine stress system during sleep. We could not believe our eyes,” Dr. Kjaerby said. “Everyone had thought the system would be quiet. And now we have found out that it completely controls the microarchitecture of sleep.”
Those noradrenaline levels rise and fall like waves every 30 seconds during non-REM (NREM) sleep. At each “peak” the brain is briefly awake, and at each “valley” it is asleep. Typically, these awakenings are so brief that the sleeping subject does not notice. But the higher the rise, the longer the awakening – and the more likely the sleeper may notice.
During the valleys, or when norepinephrine drops, so-called sleep spindles occur.
“These are short oscillatory bursts of brain activity linked to memory consolidation,” Dr. Kjaerby said. Occasionally there is a “deep valley,” lasting 3-5 minutes, leading to more sleep spindles. The mice with the most deep valleys also had the best memories, the researchers noted.
“We have shown that the amount of these super-boosts of sleep spindles, and not REM sleep, defines how well you remember the experiences you had prior to going to sleep,” said Dr. Kjaerby.
Deep valleys were followed by longer awakenings, the researchers observed. So, the longer the valley, the longer the awakening – and the better the memory boost. This means that, though restless sleep is not good, waking up briefly may be a natural part of memory-related sleep phases and may even mean you’ve slept well.
What happens in our brains when we sleep: Piecing it together
The findings fit with previous clinical data that shows we wake up roughly 100-plus times a night, mostly during NREM sleep stage 2 (the spindle-rich sleep stage), Dr. Kjaerby said.
Still, more research on these small awakenings is needed, Dr. Kjaerby said, noting that professor Maiken Nedergaard, MD, another author of this study, has found that the brain cleans up waste products through a rinsing fluid system.
“It remains a puzzle why the fluid system is so active when we sleep,” Dr. Kjaerby said. “We believe these short awakenings could potentially be the key to answering this question.”
A version of this article first appeared on WebMD.com.
FROM NATURE NEUROSCIENCE