Neurology

Damaged mitochondrial DNA (mtDNA) initiates and spreads Parkinson’s disease (PD) pathology, potentially opening new avenues for early diagnosis, disease monitoring, and drug development.

While defects in mitochondrial functions and in mitochondrial DNA have been implicated in PD in the past, the current study demonstrates “for the first time how damaged mitochondrial DNA can underlie the mechanisms of PD initiation and spread in brain,” lead investigator Shohreh Issazadeh-Navikas, PhD, with the University of Copenhagen, told this news organization.

“This has direct implication for clinical diagnosis” – if damaged mtDNA can be detected in blood, it could serve as an early biomarker for disease, she explained.

The study was published online in Molecular Psychiatry.
 

“Infectious-like” spread of PD pathology

In earlier work, the researchers identified dysregulated interferon-beta (IFN-beta) signaling as a “top candidate pathway” associated with sporadic PD and its progression to PD with dementia (PDD).

In mice PD models that were deficient in IFN-beta signaling, the investigators showed that neuronal IFN-beta is required to maintain mitochondrial homeostasis and metabolism.

Lack of neuronal IFN-beta or disruption of its downstream signaling causes the accumulation of damaged mitochondria with excessive oxidative stress and insufficient adenosine triphosphate production.

In the current study, using postmortem brain tissue samples from patients with sporadic PD, they confirmed that there were deletions of mtDNA in the medial frontal gyrus, a region implicated in cognitive impairments in PD, suggesting a potential role of damaged mtDNA in disease pathophysiology.

They also identified mtDNA deletions in a “hotspot” in complex I respiratory chain subunits that were associated with dysregulation of oxidative stress and DNA damage response pathways in cohorts with sporadic PD and PDD.

They confirmed the contribution of mtDNA damage to PD pathology in the PD mouse models. They showed that lack of neuronal IFN-beta signaling leads to oxidative damage and mutations in mtDNA in neurons, which are subsequently released outside the neurons.

Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. It also caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an “infectious-like” manner, the researchers report.

Further study revealed that the mechanism through which damaged mtDNA causes pathology in healthy neurons involves dual activation of Toll-like receptor (TLR) 9 and 4 pathways, leading to increased oxidative stress and neuronal cell death, respectively.

“Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, ribosomal protein S3, as a key protein involved in recognizing and extruding damaged mtDNA,” the investigators write.

In the future they plan to investigate how mtDNA damage can serve as a predictive marker for different disease stages and progression and to explore potential therapeutic strategies aimed at restoring normal mitochondrial function to rectify the mitochondrial dysfunctions implicated in PD.
 

Making a comeback?

Commenting on the research for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, noted that the role of mitochondria in PD is “like a starlet that burst onto the scene in the 80s, faded into obscurity, and through diligence and continued research has moved beyond being a solid character actor and is reemerging as a force to reckon with.

“This paper only adds to the allure that mitochondria may have in contributing to PD by providing evidence of a novel process by which mitochondria may be not only contributing to PD and loss of dopamine neurons but may play a larger role in the subsequent effects that many people with PD experience – dementia,” Dr. Beck said.

He noted that the authors identified several proteins as facilitating the neurodegeneration that is wrought by damaged mitochondrial DNA.

“These could be potential targets for future drug development. In addition, this work implicates alterations in immune signaling and drugs in development to target inflammatory responses may also bring ancillary benefit,” Dr. Beck said.

However, he said, “while very interesting findings, this is really the first effort that demonstrates how damaged mitochondrial DNA may contribute to neurodegeneration in the context of PD and PD dementia. Further work needs to validate these findings as well as to elucidate mechanisms underlying the propagation of the mitochondrial DNA from cell to cell.”

Funding for this research was provided by the European Union’s Horizon 2020 Research and Innovation Program, the Lundbeck Foundation, and the Danish Council for Independent Research–Medicine. Dr. Issazadeh-Navikas and Dr. Beck have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Damaged mitochondrial DNA (mtDNA) initiates and spreads Parkinson’s disease (PD) pathology, potentially opening new avenues for early diagnosis, disease monitoring, and drug development.

While defects in mitochondrial functions and in mitochondrial DNA have been implicated in PD in the past, the current study demonstrates “for the first time how damaged mitochondrial DNA can underlie the mechanisms of PD initiation and spread in brain,” lead investigator Shohreh Issazadeh-Navikas, PhD, with the University of Copenhagen, told this news organization.

“This has direct implication for clinical diagnosis” – if damaged mtDNA can be detected in blood, it could serve as an early biomarker for disease, she explained.

The study was published online in Molecular Psychiatry.
 

“Infectious-like” spread of PD pathology

In earlier work, the researchers identified dysregulated interferon-beta (IFN-beta) signaling as a “top candidate pathway” associated with sporadic PD and its progression to PD with dementia (PDD).

In mice PD models that were deficient in IFN-beta signaling, the investigators showed that neuronal IFN-beta is required to maintain mitochondrial homeostasis and metabolism.

Lack of neuronal IFN-beta or disruption of its downstream signaling causes the accumulation of damaged mitochondria with excessive oxidative stress and insufficient adenosine triphosphate production.

In the current study, using postmortem brain tissue samples from patients with sporadic PD, they confirmed that there were deletions of mtDNA in the medial frontal gyrus, a region implicated in cognitive impairments in PD, suggesting a potential role of damaged mtDNA in disease pathophysiology.

They also identified mtDNA deletions in a “hotspot” in complex I respiratory chain subunits that were associated with dysregulation of oxidative stress and DNA damage response pathways in cohorts with sporadic PD and PDD.

They confirmed the contribution of mtDNA damage to PD pathology in the PD mouse models. They showed that lack of neuronal IFN-beta signaling leads to oxidative damage and mutations in mtDNA in neurons, which are subsequently released outside the neurons.

Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. It also caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an “infectious-like” manner, the researchers report.

Further study revealed that the mechanism through which damaged mtDNA causes pathology in healthy neurons involves dual activation of Toll-like receptor (TLR) 9 and 4 pathways, leading to increased oxidative stress and neuronal cell death, respectively.

“Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, ribosomal protein S3, as a key protein involved in recognizing and extruding damaged mtDNA,” the investigators write.

In the future they plan to investigate how mtDNA damage can serve as a predictive marker for different disease stages and progression and to explore potential therapeutic strategies aimed at restoring normal mitochondrial function to rectify the mitochondrial dysfunctions implicated in PD.
 

Making a comeback?

Commenting on the research for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, noted that the role of mitochondria in PD is “like a starlet that burst onto the scene in the 80s, faded into obscurity, and through diligence and continued research has moved beyond being a solid character actor and is reemerging as a force to reckon with.

“This paper only adds to the allure that mitochondria may have in contributing to PD by providing evidence of a novel process by which mitochondria may be not only contributing to PD and loss of dopamine neurons but may play a larger role in the subsequent effects that many people with PD experience – dementia,” Dr. Beck said.

He noted that the authors identified several proteins as facilitating the neurodegeneration that is wrought by damaged mitochondrial DNA.

“These could be potential targets for future drug development. In addition, this work implicates alterations in immune signaling and drugs in development to target inflammatory responses may also bring ancillary benefit,” Dr. Beck said.

However, he said, “while very interesting findings, this is really the first effort that demonstrates how damaged mitochondrial DNA may contribute to neurodegeneration in the context of PD and PD dementia. Further work needs to validate these findings as well as to elucidate mechanisms underlying the propagation of the mitochondrial DNA from cell to cell.”

Funding for this research was provided by the European Union’s Horizon 2020 Research and Innovation Program, the Lundbeck Foundation, and the Danish Council for Independent Research–Medicine. Dr. Issazadeh-Navikas and Dr. Beck have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Damaged mitochondrial DNA (mtDNA) initiates and spreads Parkinson’s disease (PD) pathology, potentially opening new avenues for early diagnosis, disease monitoring, and drug development.

While defects in mitochondrial functions and in mitochondrial DNA have been implicated in PD in the past, the current study demonstrates “for the first time how damaged mitochondrial DNA can underlie the mechanisms of PD initiation and spread in brain,” lead investigator Shohreh Issazadeh-Navikas, PhD, with the University of Copenhagen, told this news organization.

“This has direct implication for clinical diagnosis” – if damaged mtDNA can be detected in blood, it could serve as an early biomarker for disease, she explained.

The study was published online in Molecular Psychiatry.
 

“Infectious-like” spread of PD pathology

In earlier work, the researchers identified dysregulated interferon-beta (IFN-beta) signaling as a “top candidate pathway” associated with sporadic PD and its progression to PD with dementia (PDD).

In mice PD models that were deficient in IFN-beta signaling, the investigators showed that neuronal IFN-beta is required to maintain mitochondrial homeostasis and metabolism.

Lack of neuronal IFN-beta or disruption of its downstream signaling causes the accumulation of damaged mitochondria with excessive oxidative stress and insufficient adenosine triphosphate production.

In the current study, using postmortem brain tissue samples from patients with sporadic PD, they confirmed that there were deletions of mtDNA in the medial frontal gyrus, a region implicated in cognitive impairments in PD, suggesting a potential role of damaged mtDNA in disease pathophysiology.

They also identified mtDNA deletions in a “hotspot” in complex I respiratory chain subunits that were associated with dysregulation of oxidative stress and DNA damage response pathways in cohorts with sporadic PD and PDD.

They confirmed the contribution of mtDNA damage to PD pathology in the PD mouse models. They showed that lack of neuronal IFN-beta signaling leads to oxidative damage and mutations in mtDNA in neurons, which are subsequently released outside the neurons.

Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. It also caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an “infectious-like” manner, the researchers report.

Further study revealed that the mechanism through which damaged mtDNA causes pathology in healthy neurons involves dual activation of Toll-like receptor (TLR) 9 and 4 pathways, leading to increased oxidative stress and neuronal cell death, respectively.

“Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, ribosomal protein S3, as a key protein involved in recognizing and extruding damaged mtDNA,” the investigators write.

In the future they plan to investigate how mtDNA damage can serve as a predictive marker for different disease stages and progression and to explore potential therapeutic strategies aimed at restoring normal mitochondrial function to rectify the mitochondrial dysfunctions implicated in PD.
 

Making a comeback?

Commenting on the research for this news organization, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, noted that the role of mitochondria in PD is “like a starlet that burst onto the scene in the 80s, faded into obscurity, and through diligence and continued research has moved beyond being a solid character actor and is reemerging as a force to reckon with.

“This paper only adds to the allure that mitochondria may have in contributing to PD by providing evidence of a novel process by which mitochondria may be not only contributing to PD and loss of dopamine neurons but may play a larger role in the subsequent effects that many people with PD experience – dementia,” Dr. Beck said.

He noted that the authors identified several proteins as facilitating the neurodegeneration that is wrought by damaged mitochondrial DNA.

“These could be potential targets for future drug development. In addition, this work implicates alterations in immune signaling and drugs in development to target inflammatory responses may also bring ancillary benefit,” Dr. Beck said.

However, he said, “while very interesting findings, this is really the first effort that demonstrates how damaged mitochondrial DNA may contribute to neurodegeneration in the context of PD and PD dementia. Further work needs to validate these findings as well as to elucidate mechanisms underlying the propagation of the mitochondrial DNA from cell to cell.”

Funding for this research was provided by the European Union’s Horizon 2020 Research and Innovation Program, the Lundbeck Foundation, and the Danish Council for Independent Research–Medicine. Dr. Issazadeh-Navikas and Dr. Beck have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Lead is significantly more harmful to the health of children and adults across the world than previously thought. This conclusion is suggested by a modeling study presented by Norwegian development economist Bjorn Larsen and the Colombian environmental specialist for lead Ernesto Sánchez-Triana, PhD, in a presentation to the World Bank. Their work was published in The Lancet Planetary Health.

As Mr. Larsen and Mr. Sánchez-Triana report, the economic consequences of increased exposure to lead are already immense, especially in low- and middle-income countries (LMICs). The study was financed by the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program.
 

Intellectual, cardiovascular effects

“It is a very important publication that affects all of us,” pediatrician Stephan Böse-O’Reilly, MD, of the Institute and Polyclinic for Occupational, Social, and Environmental Health at Ludwig Maximilian University Hospital in Munich, Germany, said in an interview. “The study, the results of which I think are very reliable, shows that elevated levels of lead in the blood have a much more drastic effect on children’s intelligence than we previously thought.”

It is well known that lead affects the antenatal and postnatal cognitive development of children, Dr. Böse-O’Reilly explained. But the extent of this effect has quite clearly been underestimated before now.

On the other hand, Mr. Larsen and Mr. Sánchez-Triana’s work could prove that lead may lead to more cardiovascular diseases in adulthood. “We already knew that increased exposure to lead increased the risk of high blood pressure and, as a result, mortality,” said Dr. Böse-O’Reilly. “This study now very clearly shows that the risk of arteriosclerosis, for example, also increases through lead exposure.”
 

Figures from 2019

“For the first time, to our knowledge, we aimed to estimate the global burden and cost of IQ loss and cardiovascular disease mortality from lead exposure,” wrote Mr. Larsen and Mr. Sánchez-Triana. For their calculations, the scientists used blood lead level estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.

They estimated IQ loss in children younger than 5 years using the internationally recognized blood lead level–IQ loss function. The researchers subsequently estimated the cost of this IQ loss based on the loss in lifetime income, presented as cost in U.S. dollars and percentage of gross domestic product (GDP).

Mr. Larsen and Mr. Sánchez-Triana estimated cardiovascular deaths caused by lead exposure in adults aged 25 years or older using a model that captures the effects of lead exposure on cardiovascular disease mortality that is mediated through mechanisms other than hypertension.

Finally, they used the statistical life expectancy to estimate the welfare cost of premature mortality, also presented as cost in U.S. dollars and percentage of GDP. All estimates were calculated according to the World Bank income classification for 2019.
 

Millions of deaths

As reported by Mr. Larsen and Mr. Sánchez-Triana, children younger than 5 years lost an estimated 765 million IQ points worldwide because of lead exposure in this period. In 2019, 5,545,000 adults died from cardiovascular diseases caused by lead exposure. The scientists recorded 729 million of the IQ points lost (95.3%) and 5,004,000 (90.2%) of the deaths as occurring in LMICs.

The IQ loss here was nearly 80% higher than a previous estimate, wrote Mr. Larsen and Mr. Sánchez-Triana. The number of cardiovascular disease deaths they determined was six times higher than the GBD 2019 estimate.

“These are results with which the expert societies, especially the German Society of Pediatrics and Adolescent Medicine and the German Cardiac Society, and the corresponding professional associations need to concern themselves,” said Dr. Böse-O’Reilly.

Although blood lead concentrations have declined substantially since the phase-out of leaded gasoline, especially in Western countries, lead still represents a major health issue because it stays in the bones for decades.

European situation moderate

“We need a broad discussion on questions such as whether lead levels should be included in prophylactic assessments in certain age groups, what blood level is even tolerable, and in what situation medicinal therapy with chelating agents would possibly be appropriate,” said Dr. Böse-O’Reilly.

“Of course, we cannot answer these questions on the basis of one individual study,” he added. “However, the work in question definitely illustrates how dangerous lead can be and that we need further research into the actual burden and the best preventive measures.”

In this respect, the situation in Europe is still comparatively moderate. “Globally, lead exposure has risen in recent years,” said Dr. Böse-O’Reilly. According to an investigation by the Planet Earth Foundation, outside of the European Union, lead can increasingly be found in toys, spices, and cooking utensils, for example.

“Especially in lower-income countries, there is a lack of consumer protection or a good monitoring program like we have here in the EU,” said Dr. Böse-O’Reilly. In these countries, lead is sometimes added to spices by unscrupulous retailers to make the color more intense or to simply add to its weight to gain more profit.

Recycling lead-acid batteries or other electrical waste, often transferred to poorer countries, constitutes a large problem. “In general, children in Germany have a blood lead level of less than 1 mcg/dL,” explained Dr. Böse-O’Reilly. “In some regions of Indonesia, where these recycling factories are located, more than 50% of children have levels of more than 20 mcg/dL.”
 

Particulate matter

According to Mr. Larsen and Mr. Sánchez-Triana, the global cost of increased lead exposure was around $6 trillion USD in 2019, which was equivalent to 6.9% of global GDP. About 77% of the cost ($4.62 trillion USD) comprised the welfare costs of cardiovascular disease mortality, and 23% ($1.38 trillion USD) comprised the present value of future income losses because of IQ loss in children.

“Our findings suggest that global lead exposure has health and economic costs on par with PM2.5 air pollution,” wrote the authors. This places lead as an environmental risk factor on par with particulate matter and above that of air pollution from solid fuels, ahead of unsafe drinking water, unhygienic sanitation, or insufficient handwashing.

“This finding is in contrast to that of GBD 2019, which ranked lead exposure as a distant fourth environmental risk factor, due to not accounting for IQ loss in children – other than idiopathic developmental intellectual disability in a small subset of children – and reporting a substantially lower estimate of adult cardiovascular disease mortality,” wrote Mr. Larsen and Mr. Sánchez-Triana.

“A central implication for future research and policy is that LMICs bear an extraordinarily large share of the health and cost burden of lead exposure,” wrote the authors. Consequently, improved quality of blood lead level measurements and identification of sources containing lead are urgently needed there.
 

Improved recycling methods

Dr. Böse-O’Reilly would like an increased focus on children. “If children’s cognitive skills are lost, this of course has a long-term effect on a country’s economic position,” he said. “Precisely that which LMICs actually need for their development is being stripped from them.

“We should think long and hard about whether we really need to send so much of our electrical waste and so many old cars to poorer countries, where they are incorrectly recycled,” he warned. “We should at least give the LMICs the support necessary for them to be able to process lead-containing products in the future so that less lead makes it into the environment.

“Through these global cycles, we all contribute a lot toward the worldwide lead burden,” Dr. Böse-O’Reilly said. “In my opinion, the German Supply Chain Act is therefore definitely sensible. Not only does it protect our own economy, but it also protects the health of people in other countries.”

This article was translated from Medscape’s German Edition. A version of this article appeared on Medscape.com.

Lead is significantly more harmful to the health of children and adults across the world than previously thought. This conclusion is suggested by a modeling study presented by Norwegian development economist Bjorn Larsen and the Colombian environmental specialist for lead Ernesto Sánchez-Triana, PhD, in a presentation to the World Bank. Their work was published in The Lancet Planetary Health.

As Mr. Larsen and Mr. Sánchez-Triana report, the economic consequences of increased exposure to lead are already immense, especially in low- and middle-income countries (LMICs). The study was financed by the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program.
 

Intellectual, cardiovascular effects

“It is a very important publication that affects all of us,” pediatrician Stephan Böse-O’Reilly, MD, of the Institute and Polyclinic for Occupational, Social, and Environmental Health at Ludwig Maximilian University Hospital in Munich, Germany, said in an interview. “The study, the results of which I think are very reliable, shows that elevated levels of lead in the blood have a much more drastic effect on children’s intelligence than we previously thought.”

It is well known that lead affects the antenatal and postnatal cognitive development of children, Dr. Böse-O’Reilly explained. But the extent of this effect has quite clearly been underestimated before now.

On the other hand, Mr. Larsen and Mr. Sánchez-Triana’s work could prove that lead may lead to more cardiovascular diseases in adulthood. “We already knew that increased exposure to lead increased the risk of high blood pressure and, as a result, mortality,” said Dr. Böse-O’Reilly. “This study now very clearly shows that the risk of arteriosclerosis, for example, also increases through lead exposure.”
 

Figures from 2019

“For the first time, to our knowledge, we aimed to estimate the global burden and cost of IQ loss and cardiovascular disease mortality from lead exposure,” wrote Mr. Larsen and Mr. Sánchez-Triana. For their calculations, the scientists used blood lead level estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.

They estimated IQ loss in children younger than 5 years using the internationally recognized blood lead level–IQ loss function. The researchers subsequently estimated the cost of this IQ loss based on the loss in lifetime income, presented as cost in U.S. dollars and percentage of gross domestic product (GDP).

Mr. Larsen and Mr. Sánchez-Triana estimated cardiovascular deaths caused by lead exposure in adults aged 25 years or older using a model that captures the effects of lead exposure on cardiovascular disease mortality that is mediated through mechanisms other than hypertension.

Finally, they used the statistical life expectancy to estimate the welfare cost of premature mortality, also presented as cost in U.S. dollars and percentage of GDP. All estimates were calculated according to the World Bank income classification for 2019.
 

Millions of deaths

As reported by Mr. Larsen and Mr. Sánchez-Triana, children younger than 5 years lost an estimated 765 million IQ points worldwide because of lead exposure in this period. In 2019, 5,545,000 adults died from cardiovascular diseases caused by lead exposure. The scientists recorded 729 million of the IQ points lost (95.3%) and 5,004,000 (90.2%) of the deaths as occurring in LMICs.

The IQ loss here was nearly 80% higher than a previous estimate, wrote Mr. Larsen and Mr. Sánchez-Triana. The number of cardiovascular disease deaths they determined was six times higher than the GBD 2019 estimate.

“These are results with which the expert societies, especially the German Society of Pediatrics and Adolescent Medicine and the German Cardiac Society, and the corresponding professional associations need to concern themselves,” said Dr. Böse-O’Reilly.

Although blood lead concentrations have declined substantially since the phase-out of leaded gasoline, especially in Western countries, lead still represents a major health issue because it stays in the bones for decades.

European situation moderate

“We need a broad discussion on questions such as whether lead levels should be included in prophylactic assessments in certain age groups, what blood level is even tolerable, and in what situation medicinal therapy with chelating agents would possibly be appropriate,” said Dr. Böse-O’Reilly.

“Of course, we cannot answer these questions on the basis of one individual study,” he added. “However, the work in question definitely illustrates how dangerous lead can be and that we need further research into the actual burden and the best preventive measures.”

In this respect, the situation in Europe is still comparatively moderate. “Globally, lead exposure has risen in recent years,” said Dr. Böse-O’Reilly. According to an investigation by the Planet Earth Foundation, outside of the European Union, lead can increasingly be found in toys, spices, and cooking utensils, for example.

“Especially in lower-income countries, there is a lack of consumer protection or a good monitoring program like we have here in the EU,” said Dr. Böse-O’Reilly. In these countries, lead is sometimes added to spices by unscrupulous retailers to make the color more intense or to simply add to its weight to gain more profit.

Recycling lead-acid batteries or other electrical waste, often transferred to poorer countries, constitutes a large problem. “In general, children in Germany have a blood lead level of less than 1 mcg/dL,” explained Dr. Böse-O’Reilly. “In some regions of Indonesia, where these recycling factories are located, more than 50% of children have levels of more than 20 mcg/dL.”
 

Particulate matter

According to Mr. Larsen and Mr. Sánchez-Triana, the global cost of increased lead exposure was around $6 trillion USD in 2019, which was equivalent to 6.9% of global GDP. About 77% of the cost ($4.62 trillion USD) comprised the welfare costs of cardiovascular disease mortality, and 23% ($1.38 trillion USD) comprised the present value of future income losses because of IQ loss in children.

“Our findings suggest that global lead exposure has health and economic costs on par with PM2.5 air pollution,” wrote the authors. This places lead as an environmental risk factor on par with particulate matter and above that of air pollution from solid fuels, ahead of unsafe drinking water, unhygienic sanitation, or insufficient handwashing.

“This finding is in contrast to that of GBD 2019, which ranked lead exposure as a distant fourth environmental risk factor, due to not accounting for IQ loss in children – other than idiopathic developmental intellectual disability in a small subset of children – and reporting a substantially lower estimate of adult cardiovascular disease mortality,” wrote Mr. Larsen and Mr. Sánchez-Triana.

“A central implication for future research and policy is that LMICs bear an extraordinarily large share of the health and cost burden of lead exposure,” wrote the authors. Consequently, improved quality of blood lead level measurements and identification of sources containing lead are urgently needed there.
 

Improved recycling methods

Dr. Böse-O’Reilly would like an increased focus on children. “If children’s cognitive skills are lost, this of course has a long-term effect on a country’s economic position,” he said. “Precisely that which LMICs actually need for their development is being stripped from them.

“We should think long and hard about whether we really need to send so much of our electrical waste and so many old cars to poorer countries, where they are incorrectly recycled,” he warned. “We should at least give the LMICs the support necessary for them to be able to process lead-containing products in the future so that less lead makes it into the environment.

“Through these global cycles, we all contribute a lot toward the worldwide lead burden,” Dr. Böse-O’Reilly said. “In my opinion, the German Supply Chain Act is therefore definitely sensible. Not only does it protect our own economy, but it also protects the health of people in other countries.”

This article was translated from Medscape’s German Edition. A version of this article appeared on Medscape.com.

Lead is significantly more harmful to the health of children and adults across the world than previously thought. This conclusion is suggested by a modeling study presented by Norwegian development economist Bjorn Larsen and the Colombian environmental specialist for lead Ernesto Sánchez-Triana, PhD, in a presentation to the World Bank. Their work was published in The Lancet Planetary Health.

As Mr. Larsen and Mr. Sánchez-Triana report, the economic consequences of increased exposure to lead are already immense, especially in low- and middle-income countries (LMICs). The study was financed by the Korea Green Growth Trust Fund and the World Bank’s Pollution Management and Environmental Health Program.
 

Intellectual, cardiovascular effects

“It is a very important publication that affects all of us,” pediatrician Stephan Böse-O’Reilly, MD, of the Institute and Polyclinic for Occupational, Social, and Environmental Health at Ludwig Maximilian University Hospital in Munich, Germany, said in an interview. “The study, the results of which I think are very reliable, shows that elevated levels of lead in the blood have a much more drastic effect on children’s intelligence than we previously thought.”

It is well known that lead affects the antenatal and postnatal cognitive development of children, Dr. Böse-O’Reilly explained. But the extent of this effect has quite clearly been underestimated before now.

On the other hand, Mr. Larsen and Mr. Sánchez-Triana’s work could prove that lead may lead to more cardiovascular diseases in adulthood. “We already knew that increased exposure to lead increased the risk of high blood pressure and, as a result, mortality,” said Dr. Böse-O’Reilly. “This study now very clearly shows that the risk of arteriosclerosis, for example, also increases through lead exposure.”
 

Figures from 2019

“For the first time, to our knowledge, we aimed to estimate the global burden and cost of IQ loss and cardiovascular disease mortality from lead exposure,” wrote Mr. Larsen and Mr. Sánchez-Triana. For their calculations, the scientists used blood lead level estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.

They estimated IQ loss in children younger than 5 years using the internationally recognized blood lead level–IQ loss function. The researchers subsequently estimated the cost of this IQ loss based on the loss in lifetime income, presented as cost in U.S. dollars and percentage of gross domestic product (GDP).

Mr. Larsen and Mr. Sánchez-Triana estimated cardiovascular deaths caused by lead exposure in adults aged 25 years or older using a model that captures the effects of lead exposure on cardiovascular disease mortality that is mediated through mechanisms other than hypertension.

Finally, they used the statistical life expectancy to estimate the welfare cost of premature mortality, also presented as cost in U.S. dollars and percentage of GDP. All estimates were calculated according to the World Bank income classification for 2019.
 

Millions of deaths

As reported by Mr. Larsen and Mr. Sánchez-Triana, children younger than 5 years lost an estimated 765 million IQ points worldwide because of lead exposure in this period. In 2019, 5,545,000 adults died from cardiovascular diseases caused by lead exposure. The scientists recorded 729 million of the IQ points lost (95.3%) and 5,004,000 (90.2%) of the deaths as occurring in LMICs.

The IQ loss here was nearly 80% higher than a previous estimate, wrote Mr. Larsen and Mr. Sánchez-Triana. The number of cardiovascular disease deaths they determined was six times higher than the GBD 2019 estimate.

“These are results with which the expert societies, especially the German Society of Pediatrics and Adolescent Medicine and the German Cardiac Society, and the corresponding professional associations need to concern themselves,” said Dr. Böse-O’Reilly.

Although blood lead concentrations have declined substantially since the phase-out of leaded gasoline, especially in Western countries, lead still represents a major health issue because it stays in the bones for decades.

European situation moderate

“We need a broad discussion on questions such as whether lead levels should be included in prophylactic assessments in certain age groups, what blood level is even tolerable, and in what situation medicinal therapy with chelating agents would possibly be appropriate,” said Dr. Böse-O’Reilly.

“Of course, we cannot answer these questions on the basis of one individual study,” he added. “However, the work in question definitely illustrates how dangerous lead can be and that we need further research into the actual burden and the best preventive measures.”

In this respect, the situation in Europe is still comparatively moderate. “Globally, lead exposure has risen in recent years,” said Dr. Böse-O’Reilly. According to an investigation by the Planet Earth Foundation, outside of the European Union, lead can increasingly be found in toys, spices, and cooking utensils, for example.

“Especially in lower-income countries, there is a lack of consumer protection or a good monitoring program like we have here in the EU,” said Dr. Böse-O’Reilly. In these countries, lead is sometimes added to spices by unscrupulous retailers to make the color more intense or to simply add to its weight to gain more profit.

Recycling lead-acid batteries or other electrical waste, often transferred to poorer countries, constitutes a large problem. “In general, children in Germany have a blood lead level of less than 1 mcg/dL,” explained Dr. Böse-O’Reilly. “In some regions of Indonesia, where these recycling factories are located, more than 50% of children have levels of more than 20 mcg/dL.”
 

Particulate matter

According to Mr. Larsen and Mr. Sánchez-Triana, the global cost of increased lead exposure was around $6 trillion USD in 2019, which was equivalent to 6.9% of global GDP. About 77% of the cost ($4.62 trillion USD) comprised the welfare costs of cardiovascular disease mortality, and 23% ($1.38 trillion USD) comprised the present value of future income losses because of IQ loss in children.

“Our findings suggest that global lead exposure has health and economic costs on par with PM2.5 air pollution,” wrote the authors. This places lead as an environmental risk factor on par with particulate matter and above that of air pollution from solid fuels, ahead of unsafe drinking water, unhygienic sanitation, or insufficient handwashing.

“This finding is in contrast to that of GBD 2019, which ranked lead exposure as a distant fourth environmental risk factor, due to not accounting for IQ loss in children – other than idiopathic developmental intellectual disability in a small subset of children – and reporting a substantially lower estimate of adult cardiovascular disease mortality,” wrote Mr. Larsen and Mr. Sánchez-Triana.

“A central implication for future research and policy is that LMICs bear an extraordinarily large share of the health and cost burden of lead exposure,” wrote the authors. Consequently, improved quality of blood lead level measurements and identification of sources containing lead are urgently needed there.
 

Improved recycling methods

Dr. Böse-O’Reilly would like an increased focus on children. “If children’s cognitive skills are lost, this of course has a long-term effect on a country’s economic position,” he said. “Precisely that which LMICs actually need for their development is being stripped from them.

“We should think long and hard about whether we really need to send so much of our electrical waste and so many old cars to poorer countries, where they are incorrectly recycled,” he warned. “We should at least give the LMICs the support necessary for them to be able to process lead-containing products in the future so that less lead makes it into the environment.

“Through these global cycles, we all contribute a lot toward the worldwide lead burden,” Dr. Böse-O’Reilly said. “In my opinion, the German Supply Chain Act is therefore definitely sensible. Not only does it protect our own economy, but it also protects the health of people in other countries.”

This article was translated from Medscape’s German Edition. A version of this article appeared on Medscape.com.

TOPLINE:

People with a history of depression or stress were significantly more likely to be diagnosed with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) later in life compared with those without either condition, a new study found.

METHODOLOGY:

• Longitudinal cohort study of 1,362,548 people with records in the Region Stockholm administrative health care database with a diagnosis of stress-induced exhaustion disorder (SED), depression, or both between 2012 and 2013.
• Cohort followed for diagnosis of MCI or AD between 2014 and 2022.

TAKEAWAY:

• SED diagnosed in 0.3%, depression in 2.9% and both SED and depression in 0.1%
• Compared with people without SED or depression, AD risk was more than double in patients with SED (adjusted odds ratio [aOR], 2.45; 99% confidence interval [CI], 1.22-4.91) or depression (aOR, 2.32; 99% CI, 1.85-2.90) and four times higher in patients with both SED and depression (aOR, 4.00; 99% CI, 1.67-9.58)
• Risk for MCI was also higher in people with SED (aOR, 1.87; 99% CI,1.20-2.91), depression (aOR, 2.85; 99% CI, 2.53-3.22) or both SED and depression (aOR, 3.87; 99% CI, 2.39-6.27) vs patients with no history of SED or depression.
• Only patients with depression had a higher risk for another dementia type (aOR, 2.39; 99% CI, 1.92-2.96).

IN PRACTICE:

“Future studies should examine the possibility that symptoms of depression and/or chronic stress could be prodromal symptoms of dementia rather than risk factors,” study authors wrote.

SOURCE:

The study was conducted by Johanna Wallensten, doctoral student, department of clinical sciences, Danderyd Hospital, Stockholm, and colleagues and funded by the Karolinska Institute. It was published online in Alzheimer’s Research and Therapy.

LIMITATIONS:

Use of a health care registry could have led to over- or underestimation of depression, MCI and AD. The study probably captures most people with depression but not most people with depressive symptoms.

DISCLOSURES:

The authors reported no relevant conflicts.

A version of this article appeared on Medscape.com.

TOPLINE:

People with a history of depression or stress were significantly more likely to be diagnosed with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) later in life compared with those without either condition, a new study found.

METHODOLOGY:

• Longitudinal cohort study of 1,362,548 people with records in the Region Stockholm administrative health care database with a diagnosis of stress-induced exhaustion disorder (SED), depression, or both between 2012 and 2013.
• Cohort followed for diagnosis of MCI or AD between 2014 and 2022.

TAKEAWAY:

• SED diagnosed in 0.3%, depression in 2.9% and both SED and depression in 0.1%
• Compared with people without SED or depression, AD risk was more than double in patients with SED (adjusted odds ratio [aOR], 2.45; 99% confidence interval [CI], 1.22-4.91) or depression (aOR, 2.32; 99% CI, 1.85-2.90) and four times higher in patients with both SED and depression (aOR, 4.00; 99% CI, 1.67-9.58)
• Risk for MCI was also higher in people with SED (aOR, 1.87; 99% CI,1.20-2.91), depression (aOR, 2.85; 99% CI, 2.53-3.22) or both SED and depression (aOR, 3.87; 99% CI, 2.39-6.27) vs patients with no history of SED or depression.
• Only patients with depression had a higher risk for another dementia type (aOR, 2.39; 99% CI, 1.92-2.96).

IN PRACTICE:

“Future studies should examine the possibility that symptoms of depression and/or chronic stress could be prodromal symptoms of dementia rather than risk factors,” study authors wrote.

SOURCE:

The study was conducted by Johanna Wallensten, doctoral student, department of clinical sciences, Danderyd Hospital, Stockholm, and colleagues and funded by the Karolinska Institute. It was published online in Alzheimer’s Research and Therapy.

LIMITATIONS:

Use of a health care registry could have led to over- or underestimation of depression, MCI and AD. The study probably captures most people with depression but not most people with depressive symptoms.

DISCLOSURES:

The authors reported no relevant conflicts.

A version of this article appeared on Medscape.com.

TOPLINE:

People with a history of depression or stress were significantly more likely to be diagnosed with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) later in life compared with those without either condition, a new study found.

METHODOLOGY:

• Longitudinal cohort study of 1,362,548 people with records in the Region Stockholm administrative health care database with a diagnosis of stress-induced exhaustion disorder (SED), depression, or both between 2012 and 2013.
• Cohort followed for diagnosis of MCI or AD between 2014 and 2022.

TAKEAWAY:

• SED diagnosed in 0.3%, depression in 2.9% and both SED and depression in 0.1%
• Compared with people without SED or depression, AD risk was more than double in patients with SED (adjusted odds ratio [aOR], 2.45; 99% confidence interval [CI], 1.22-4.91) or depression (aOR, 2.32; 99% CI, 1.85-2.90) and four times higher in patients with both SED and depression (aOR, 4.00; 99% CI, 1.67-9.58)
• Risk for MCI was also higher in people with SED (aOR, 1.87; 99% CI,1.20-2.91), depression (aOR, 2.85; 99% CI, 2.53-3.22) or both SED and depression (aOR, 3.87; 99% CI, 2.39-6.27) vs patients with no history of SED or depression.
• Only patients with depression had a higher risk for another dementia type (aOR, 2.39; 99% CI, 1.92-2.96).

IN PRACTICE:

“Future studies should examine the possibility that symptoms of depression and/or chronic stress could be prodromal symptoms of dementia rather than risk factors,” study authors wrote.

SOURCE:

The study was conducted by Johanna Wallensten, doctoral student, department of clinical sciences, Danderyd Hospital, Stockholm, and colleagues and funded by the Karolinska Institute. It was published online in Alzheimer’s Research and Therapy.

LIMITATIONS:

Use of a health care registry could have led to over- or underestimation of depression, MCI and AD. The study probably captures most people with depression but not most people with depressive symptoms.

DISCLOSURES:

The authors reported no relevant conflicts.

A version of this article appeared on Medscape.com.

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

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

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

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

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

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

TOPLINE:

Loneliness is associated with a higher risk of developing Parkinson’s disease (PD) across demographic groups and independent of other risk factors, data from nearly 500,000 U.K. adults suggest.

METHODOLOGY:

• Loneliness is associated with illness and death, including higher risk of neurodegenerative diseases, but no study has examined whether the association between loneliness and detrimental outcomes extends to PD.
• The current analysis included 491,603 U.K. Biobank participants (mean age, 56; 54% women) without a diagnosis of PD at baseline.
• Loneliness was assessed by a single question at baseline and incident PD was ascertained via health records over 15 years.
• Researchers assessed whether the association between loneliness and PD was moderated by age, sex, or genetic risk and whether the association was accounted for by sociodemographic factors; behavioral, mental, physical, or social factors; or genetic risk.

TAKEAWAY:

• Roughly 19% of the cohort reported being lonely. Compared with those who were not lonely, those who did report being lonely were slightly younger and were more likely to be women. They also had fewer resources, more health risk behaviors (current smoker and physically inactive), and worse physical and mental health.
• Over 15+ years of follow-up, 2,822 participants developed PD (incidence rate: 47 per 100,000 person-years). Compared with those who did not develop PD, those who did were older and more likely to be male, former smokers, have higher BMI and PD polygenetic risk score, and to have diabetes, hypertension, myocardial infarction or stroke, anxiety, or depression.
• In the primary analysis, individuals who reported being lonely had a higher risk for PD (hazard ratio, 1.37) – an association that remained after accounting for demographic and socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, BMI, diabetes, hypertension, stroke, myocardial infarction, depression, and having ever seen a psychiatrist (fully adjusted HR, 1.25). 
• The association between loneliness and incident PD was not moderated by sex, age, or polygenetic risk score.
• Contrary to expectations for a prodromal syndrome, loneliness was not associated with incident PD in the first 5 years after baseline but was associated with PD risk in the subsequent 10 years of follow-up (HR, 1.32).

IN PRACTICE:

“Our findings complement other evidence that loneliness is a psychosocial determinant of health associated with increased risk of morbidity and mortality [and] supports recent calls for the protective and healing effects of personally meaningful social connection,” the authors write.

SOURCE:

The study, with first author Antonio Terracciano, PhD, of Florida State University College of Medicine, Tallahassee, was published online  in JAMA Neurology.

LIMITATIONS:

This observational study could not determine causality or whether reverse causality could explain the association. Loneliness was assessed by a single yes/no question. PD diagnosis relied on hospital admission and death records and may have missed early PD diagnoses.

DISCLOSURES:

Funding for the study was provided by the National Institutes of Health and National Institute on Aging. The authors report no relevant financial relationships.

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

TOPLINE:

Loneliness is associated with a higher risk of developing Parkinson’s disease (PD) across demographic groups and independent of other risk factors, data from nearly 500,000 U.K. adults suggest.

METHODOLOGY:

• Loneliness is associated with illness and death, including higher risk of neurodegenerative diseases, but no study has examined whether the association between loneliness and detrimental outcomes extends to PD.
• The current analysis included 491,603 U.K. Biobank participants (mean age, 56; 54% women) without a diagnosis of PD at baseline.
• Loneliness was assessed by a single question at baseline and incident PD was ascertained via health records over 15 years.
• Researchers assessed whether the association between loneliness and PD was moderated by age, sex, or genetic risk and whether the association was accounted for by sociodemographic factors; behavioral, mental, physical, or social factors; or genetic risk.

TAKEAWAY:

• Roughly 19% of the cohort reported being lonely. Compared with those who were not lonely, those who did report being lonely were slightly younger and were more likely to be women. They also had fewer resources, more health risk behaviors (current smoker and physically inactive), and worse physical and mental health.
• Over 15+ years of follow-up, 2,822 participants developed PD (incidence rate: 47 per 100,000 person-years). Compared with those who did not develop PD, those who did were older and more likely to be male, former smokers, have higher BMI and PD polygenetic risk score, and to have diabetes, hypertension, myocardial infarction or stroke, anxiety, or depression.
• In the primary analysis, individuals who reported being lonely had a higher risk for PD (hazard ratio, 1.37) – an association that remained after accounting for demographic and socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, BMI, diabetes, hypertension, stroke, myocardial infarction, depression, and having ever seen a psychiatrist (fully adjusted HR, 1.25). 
• The association between loneliness and incident PD was not moderated by sex, age, or polygenetic risk score.
• Contrary to expectations for a prodromal syndrome, loneliness was not associated with incident PD in the first 5 years after baseline but was associated with PD risk in the subsequent 10 years of follow-up (HR, 1.32).

IN PRACTICE:

“Our findings complement other evidence that loneliness is a psychosocial determinant of health associated with increased risk of morbidity and mortality [and] supports recent calls for the protective and healing effects of personally meaningful social connection,” the authors write.

SOURCE:

The study, with first author Antonio Terracciano, PhD, of Florida State University College of Medicine, Tallahassee, was published online  in JAMA Neurology.

LIMITATIONS:

This observational study could not determine causality or whether reverse causality could explain the association. Loneliness was assessed by a single yes/no question. PD diagnosis relied on hospital admission and death records and may have missed early PD diagnoses.

DISCLOSURES:

Funding for the study was provided by the National Institutes of Health and National Institute on Aging. The authors report no relevant financial relationships.

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

TOPLINE:

Loneliness is associated with a higher risk of developing Parkinson’s disease (PD) across demographic groups and independent of other risk factors, data from nearly 500,000 U.K. adults suggest.

METHODOLOGY:

• Loneliness is associated with illness and death, including higher risk of neurodegenerative diseases, but no study has examined whether the association between loneliness and detrimental outcomes extends to PD.
• The current analysis included 491,603 U.K. Biobank participants (mean age, 56; 54% women) without a diagnosis of PD at baseline.
• Loneliness was assessed by a single question at baseline and incident PD was ascertained via health records over 15 years.
• Researchers assessed whether the association between loneliness and PD was moderated by age, sex, or genetic risk and whether the association was accounted for by sociodemographic factors; behavioral, mental, physical, or social factors; or genetic risk.

TAKEAWAY:

• Roughly 19% of the cohort reported being lonely. Compared with those who were not lonely, those who did report being lonely were slightly younger and were more likely to be women. They also had fewer resources, more health risk behaviors (current smoker and physically inactive), and worse physical and mental health.
• Over 15+ years of follow-up, 2,822 participants developed PD (incidence rate: 47 per 100,000 person-years). Compared with those who did not develop PD, those who did were older and more likely to be male, former smokers, have higher BMI and PD polygenetic risk score, and to have diabetes, hypertension, myocardial infarction or stroke, anxiety, or depression.
• In the primary analysis, individuals who reported being lonely had a higher risk for PD (hazard ratio, 1.37) – an association that remained after accounting for demographic and socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, BMI, diabetes, hypertension, stroke, myocardial infarction, depression, and having ever seen a psychiatrist (fully adjusted HR, 1.25). 
• The association between loneliness and incident PD was not moderated by sex, age, or polygenetic risk score.
• Contrary to expectations for a prodromal syndrome, loneliness was not associated with incident PD in the first 5 years after baseline but was associated with PD risk in the subsequent 10 years of follow-up (HR, 1.32).

IN PRACTICE:

“Our findings complement other evidence that loneliness is a psychosocial determinant of health associated with increased risk of morbidity and mortality [and] supports recent calls for the protective and healing effects of personally meaningful social connection,” the authors write.

SOURCE:

The study, with first author Antonio Terracciano, PhD, of Florida State University College of Medicine, Tallahassee, was published online  in JAMA Neurology.

LIMITATIONS:

This observational study could not determine causality or whether reverse causality could explain the association. Loneliness was assessed by a single yes/no question. PD diagnosis relied on hospital admission and death records and may have missed early PD diagnoses.

DISCLOSURES:

Funding for the study was provided by the National Institutes of Health and National Institute on Aging. The authors report no relevant financial relationships.

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

This transcript has been edited for clarity.

On May 3, 2023, Surgeon General Vivek Murthy issued an advisory raising an alarm about what he called an “epidemic of loneliness” in the United States.

Now, I am not saying that Vivek Murthy read my book, “How Medicine Works and When It Doesn’t” – released in January and available in bookstores now – where, in chapter 11, I call attention to the problem of loneliness and its relationship to the exponential rise in deaths of despair. But Vivek, if you did, let me know. I could use the publicity.

No, of course the idea that loneliness is a public health issue is not new, but I’m glad to see it finally getting attention. At this point, studies have linked loneliness to heart disease, stroke, dementia, and premature death. And now, according to a new study, loneliness may be linked to Parkinson’s disease.

The UK Biobank is really a treasure trove of data for epidemiologists. I must see three to four studies a week coming out of this mega-dataset. This one, appearing in JAMA Neurology, caught my eye for its focus specifically on loneliness as a risk factor – something I’m hoping to see more of in the future.

The study examines data from just under 500,000 individuals in the United Kingdom who answered a survey including the question “Do you often feel lonely?” between 2006 and 2010; 18.4% of people answered yes. Individuals’ electronic health record data were then monitored over time to see who would get a new diagnosis code consistent with Parkinson’s disease. Through 2021, 2822 people did – that’s just over half a percent.

So, now we do the statistics thing. Of the nonlonely folks, 2,273 went on to develop Parkinson’s disease. Of those who said they often feel lonely, 549 people did. The raw numbers here, to be honest, aren’t that compelling. Lonely people had an absolute risk for Parkinson’s disease about 0.03% higher than that of nonlonely people. Put another way, you’d need to take over 3,000 lonely souls and make them not lonely to prevent 1 case of Parkinson’s disease.

Still, the costs of loneliness are not measured exclusively in Parkinson’s disease, and I would argue that the real risks here come from other sources: alcohol abuse, drug abuse, and suicide. Nevertheless, the weak but significant association with Parkinson’s disease reminds us that loneliness is a neurologic phenomenon. There is something about social connection that affects our brain in a way that is not just spiritual; it is actually biological.

Of course, people who say they are often lonely are different in other ways from people who report not being lonely. Lonely people, in this dataset, were younger, more likely to be female, less likely to have a college degree, in worse physical health, and engaged in more high-risk health behaviors like smoking.

The authors adjusted for all of these factors and found that, on the relative scale, lonely people were still about 20%-30% more likely to develop Parkinson’s disease.

courtesy JAMA Neurology

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale University’s Clinical and Translational Research Accelerator in New Haven, Conn. He reported no relevant conflicts of interest.
 

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

This transcript has been edited for clarity.

On May 3, 2023, Surgeon General Vivek Murthy issued an advisory raising an alarm about what he called an “epidemic of loneliness” in the United States.

Now, I am not saying that Vivek Murthy read my book, “How Medicine Works and When It Doesn’t” – released in January and available in bookstores now – where, in chapter 11, I call attention to the problem of loneliness and its relationship to the exponential rise in deaths of despair. But Vivek, if you did, let me know. I could use the publicity.

No, of course the idea that loneliness is a public health issue is not new, but I’m glad to see it finally getting attention. At this point, studies have linked loneliness to heart disease, stroke, dementia, and premature death. And now, according to a new study, loneliness may be linked to Parkinson’s disease.

The UK Biobank is really a treasure trove of data for epidemiologists. I must see three to four studies a week coming out of this mega-dataset. This one, appearing in JAMA Neurology, caught my eye for its focus specifically on loneliness as a risk factor – something I’m hoping to see more of in the future.

The study examines data from just under 500,000 individuals in the United Kingdom who answered a survey including the question “Do you often feel lonely?” between 2006 and 2010; 18.4% of people answered yes. Individuals’ electronic health record data were then monitored over time to see who would get a new diagnosis code consistent with Parkinson’s disease. Through 2021, 2822 people did – that’s just over half a percent.

So, now we do the statistics thing. Of the nonlonely folks, 2,273 went on to develop Parkinson’s disease. Of those who said they often feel lonely, 549 people did. The raw numbers here, to be honest, aren’t that compelling. Lonely people had an absolute risk for Parkinson’s disease about 0.03% higher than that of nonlonely people. Put another way, you’d need to take over 3,000 lonely souls and make them not lonely to prevent 1 case of Parkinson’s disease.

Still, the costs of loneliness are not measured exclusively in Parkinson’s disease, and I would argue that the real risks here come from other sources: alcohol abuse, drug abuse, and suicide. Nevertheless, the weak but significant association with Parkinson’s disease reminds us that loneliness is a neurologic phenomenon. There is something about social connection that affects our brain in a way that is not just spiritual; it is actually biological.

Of course, people who say they are often lonely are different in other ways from people who report not being lonely. Lonely people, in this dataset, were younger, more likely to be female, less likely to have a college degree, in worse physical health, and engaged in more high-risk health behaviors like smoking.

The authors adjusted for all of these factors and found that, on the relative scale, lonely people were still about 20%-30% more likely to develop Parkinson’s disease.

courtesy JAMA Neurology

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale University’s Clinical and Translational Research Accelerator in New Haven, Conn. He reported no relevant conflicts of interest.
 

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

This transcript has been edited for clarity.

On May 3, 2023, Surgeon General Vivek Murthy issued an advisory raising an alarm about what he called an “epidemic of loneliness” in the United States.

Now, I am not saying that Vivek Murthy read my book, “How Medicine Works and When It Doesn’t” – released in January and available in bookstores now – where, in chapter 11, I call attention to the problem of loneliness and its relationship to the exponential rise in deaths of despair. But Vivek, if you did, let me know. I could use the publicity.

No, of course the idea that loneliness is a public health issue is not new, but I’m glad to see it finally getting attention. At this point, studies have linked loneliness to heart disease, stroke, dementia, and premature death. And now, according to a new study, loneliness may be linked to Parkinson’s disease.

The UK Biobank is really a treasure trove of data for epidemiologists. I must see three to four studies a week coming out of this mega-dataset. This one, appearing in JAMA Neurology, caught my eye for its focus specifically on loneliness as a risk factor – something I’m hoping to see more of in the future.

The study examines data from just under 500,000 individuals in the United Kingdom who answered a survey including the question “Do you often feel lonely?” between 2006 and 2010; 18.4% of people answered yes. Individuals’ electronic health record data were then monitored over time to see who would get a new diagnosis code consistent with Parkinson’s disease. Through 2021, 2822 people did – that’s just over half a percent.

So, now we do the statistics thing. Of the nonlonely folks, 2,273 went on to develop Parkinson’s disease. Of those who said they often feel lonely, 549 people did. The raw numbers here, to be honest, aren’t that compelling. Lonely people had an absolute risk for Parkinson’s disease about 0.03% higher than that of nonlonely people. Put another way, you’d need to take over 3,000 lonely souls and make them not lonely to prevent 1 case of Parkinson’s disease.

Still, the costs of loneliness are not measured exclusively in Parkinson’s disease, and I would argue that the real risks here come from other sources: alcohol abuse, drug abuse, and suicide. Nevertheless, the weak but significant association with Parkinson’s disease reminds us that loneliness is a neurologic phenomenon. There is something about social connection that affects our brain in a way that is not just spiritual; it is actually biological.

Of course, people who say they are often lonely are different in other ways from people who report not being lonely. Lonely people, in this dataset, were younger, more likely to be female, less likely to have a college degree, in worse physical health, and engaged in more high-risk health behaviors like smoking.

The authors adjusted for all of these factors and found that, on the relative scale, lonely people were still about 20%-30% more likely to develop Parkinson’s disease.

courtesy JAMA Neurology

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale University’s Clinical and Translational Research Accelerator in New Haven, Conn. He reported no relevant conflicts of interest.
 

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

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