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Blood transfusions linked to intracerebral hemorrhage risk
In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.
“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.
“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.
The study was published online in the Journal of the American Medical Association.
Novel finding
Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.
CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH.
The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.
The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.
Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).
“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.
There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.
The findings were robust to several of the sensitivity analyses.
A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.
This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.
The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
Worrisome finding or false alarm?
In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”
“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.
Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.
Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.
He added the current study leaves him “squarely at the corner of anxiety and skepticism.”
With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.
“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.
Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.
“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”
“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.
The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.
“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.
“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.
The study was published online in the Journal of the American Medical Association.
Novel finding
Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.
CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH.
The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.
The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.
Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).
“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.
There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.
The findings were robust to several of the sensitivity analyses.
A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.
This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.
The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
Worrisome finding or false alarm?
In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”
“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.
Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.
Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.
He added the current study leaves him “squarely at the corner of anxiety and skepticism.”
With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.
“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.
Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.
“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”
“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.
The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In an exploratory analysis, patients receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs, and were assumed to have CAA, were at a significantly increased risk of developing spontaneous ICH themselves.
“This may suggest a transfusion-transmissible agent associated with some types of spontaneous ICH, although the findings may be susceptible to selection bias and residual confounding, and further research is needed to investigate if transfusion transmission of CAA might explain this association,” the investigators noted.
“We do not think that the findings motivate a change in practice, and we should not let these results discourage otherwise indicated blood transfusion,” said lead author Jingcheng Zhao, MD, PhD, with Karolinska University Hospital Solna, Stockholm.
The study was published online in the Journal of the American Medical Association.
Novel finding
Recent evidence suggests that CAA exhibits “prion-like” transmissivity, with reports of transmission through cadaveric pituitary hormone contaminated with amyloid-beta and tau protein, dura mater grafts, and possibly neurosurgical instruments.
CAA, which is characterized by the deposition of amyloid protein in the brain, is the second most common cause of spontaneous ICH.
The researchers hypothesized that transfusion transmission of CAA may manifest through an increased risk for spontaneous ICH among transfusion recipients given blood from a donor with spontaneous ICH. To explore this hypothesis, they analyzed national registry data from Sweden and Denmark for ICH in recipients of red blood cell transfusion from donors who themselves had ICH over the years after their blood donations, with the assumption that donors with two or more ICHs would likely have CAA.
The cohort included nearly 760,000 individuals in Sweden (median age, 65 years; 59% women) and 330,000 in Denmark (median age, 64 years; 58% women), with a median follow-up of 5.8 and 6.1 years, respectively.
Receiving red blood cell transfusions from donors who later developed multiple spontaneous ICHs was associated with a greater than twofold increased risk of developing spontaneous ICH, compared with receiving a transfusion from donors without subsequent ICH (hazard ratio, 2.73; P < .001 in the Swedish cohort and HR, 2.32; P = .04 in the Danish cohort).
“The observed increased risk of spontaneous ICH associated with receiving a red blood cell transfusion from a donor who later developed multiple spontaneous ICHs, corresponding to a 30-year cumulative incidence difference of 2.3%, is a novel finding,” the researchers wrote.
There was no increase in post-transfusion ICH risk among recipients whose donors had a single post–blood-donation ICH.
The findings were robust to several of the sensitivity analyses.
A “negative” control analysis of post-transfusion ischemic stroke (instead of ICH) found no increased risk among recipients of blood from donors who had single or multiple ICHs.
This study provides “exploratory evidence of possible transfusion-transmission of a factor that causes ICHs, but more research is needed to confirm and to understand the mechanism,” said Dr. Zhao.
The researchers noted that they did not directly assess CAA but expect it would be more common among donors who develop multiple spontaneous ICHs, “as CAA-related ICH has been reported to have a 7-fold increase for recurrent ICHs, compared with non–CAA-related ICH.”
Worrisome finding or false alarm?
In an accompanying editorial, Steven Greenberg, MD, PhD, with the department of neurology, Harvard Medical School, Boston, said there are “good reasons to treat the possibility of CAA transmission via blood transfusion seriously – and good reasons to remain skeptical, at least for the present.”
“Powerful” arguments in support of the findings include the robust study methodology and the “striking” similarity in results from the two registries, which argues against a chance finding. Another is the negative control with ischemic stroke as the outcome, which argues against unsuspected confounding-causing associations with all types of stroke, Dr. Greenberg noted.
Arguments for remaining “unconvinced” of the association center on the weakness of evidence for a plausible biological mechanism for the finding, he points out. Another is the short-time course of ICHs after blood transfusion, which is “quite challenging to explain,” Dr. Greenberg said. Nearly half of the ICHs among blood recipients occurred within 5 years of transfusion, which is “dramatically” faster than the 30- to 40-year interval reported between neurosurgical exposure to cadaveric tissue and first ICH, he added.
Another related “mechanistic reservation” is the plausibility that a transmissible species of amyloid-beta could travel from blood to brain in sufficient quantities to trigger advanced CAA or Alzheimer disease pathology, he wrote.
He added the current study leaves him “squarely at the corner of anxiety and skepticism.”
With more than 10 million units of blood transfused in the United States each year, even a modest increase in risk for future brain hemorrhages or dementia conferred by “an uncommon – but as of now undetectable – donor trait would represent a substantial public health concern,” Dr. Greenberg wrote.
“From the standpoint of scientific plausibility, however, even this well-conducted analysis is at risk of representing a false alarm,” he cautioned.
Looking ahead, Dr. Greenberg said one clear direction is independent replication, ideally with datasets in which donor and recipient dementia can be reliably ascertained to assess the possibility of Alzheimer’s disease as well as CAA transmissibility.
“The other challenge is for experimental biologists to consider the alternative possibility of transfusion-related acceleration of downstream steps in the CAA-ICH pathway, such as the vessel remodeling by which amyloid beta–laden vessels proceed to rupture and bleed.”
“The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging,” Dr. Greenberg concluded.
The study was funded by grants from the Karolinska Institute, the Swedish Research Council, and Region Stockholm. Dr. Zhao and Dr. Greenberg report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From JAMA
Sedentary lifestyle tied to increased dementia risk
The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.
Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.
“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.
The findings were published online in JAMA.
A surprising find?
The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.
Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.
Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.
Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).
Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.
“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”
The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
More research welcome
Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”
“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.
It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.
“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”
The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.
Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.
“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.
The findings were published online in JAMA.
A surprising find?
The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.
Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.
Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.
Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).
Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.
“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”
The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
More research welcome
Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”
“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.
It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.
“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”
The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The study of nearly 50,000 adults in the UK Biobank shows that dementia risk increased 8% with 10 hours of sedentary time and 63% with 12 hours. That’s particularly concerning because Americans spend an average of 9.5 hours a day sitting.
Sleep wasn’t factored into the sedentary time and how someone accumulated the 10 hours – either in one continuous block or broken up throughout the day – was irrelevant.
“Our analysis cannot determine whether there is a causal link, so prescriptive conclusions are not really possible; however. I think it is very reasonable to conclude that sitting less and moving more may help reduce risk of dementia,” lead investigator David Raichlen, PhD, professor of biological sciences and anthropology, University of Southern California, Los Angeles, said in an interview.
The findings were published online in JAMA.
A surprising find?
The study is a retrospective analysis of prospectively collected data from the UK Biobank of 49,841 adults aged 60 years or older who wore an accelerometer on their wrists 24 hours a day for a week. Participants had no history of dementia when they wore the movement monitoring device.
Investigators used machine-based learning to determine sedentary time based on readings from the accelerometers. Sleep was not included as sedentary behavior.
Over a mean follow-up of 6.72 years, 414 participants were diagnosed with dementia.
Investigators found that dementia risk rises by 8% at 10 hours a day (adjusted hazard ratio, 1.08; P < .001) and 63% at 12 hours a day (aHR, 1.63; P < .001), compared with 9.27 hours a day. Those who logged 15 hours of sedentary behavior a day had more than triple the dementia risk (aHR, 3.21; P < .001).
Although previous studies had found that breaking up sedentary periods with short bursts of activity help offset some negative health effects of sitting, that wasn’t the case here. Dementia risk was elevated whether participants were sedentary for 10 uninterrupted hours or multiple sedentary periods that totaled 10 hours over the whole day.
“This was surprising,” Dr. Raichlen said. “We expected to find that patterns of sedentary behavior would play a role in risk of dementia, but once you take into account the daily volume of time spent sedentary, how you get there doesn’t seem to matter as much.”
The study did not examine how participants spent sedentary time, but an earlier study by Dr. Raichlen found that watching TV was associated with a greater risk of dementia in older adults, compared with working on a computer.
More research welcome
Dr. Raichlen noted that the number of dementia cases in the study is low and that the view of sedentary behavior is based on 1 week of accelerometer readings. A longitudinal study is needed to determine if the findings last over a longer time period.
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach for the Alzheimer’s Association, says that earlier studies reported an association between sedentary time and dementia, so these results aren’t “particularly surprising.”
“However, reports that did not find an association have also been published, so additional research on possible associations is welcome,” she said.
It’s also important to note that this observational study doesn’t establish a causal relationship between inactivity and cognitive function, which Dr. Sexton said means the influence of other dementia risk factors that are also exacerbated by sedentary behavior can’t be ruled out.
“Although results remained significant after adjusting for several of these factors, further research is required to better understand the various elements that may influence the observed relationship,” noted Dr. Sexton, who was not part of the study. “Reverse causality – that changes in the brain related to dementia are causing the sedentary behavior – cannot be ruled out.”
The study was funded by the National Institutes of Health, the state of Arizona, the Arizona Department of Health Services, and the McKnight Brain Research Foundation. Dr. Raichlen and Dr. Sexton report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA
Abdominal fat linked to lower brain volume in midlife
In a large study of healthy middle-aged adults, greater visceral and subcutaneous abdominal fat on abdominal MRI predicted brain atrophy on imaging, especially in women.
“The study shows that excess fat is bad for the brain and worse in women, including in Alzheimer’s disease risk regions,” lead author Cyrus Raji, MD, PhD, with the Mallinckrodt Institute of Radiology, Washington University, St. Louis, Mo., said in an interview.
The study was published online in the journal Aging and Disease
Modifiable risk factor
Multiple studies have suggested a connection between body fat accumulation and increased dementia risk. But few have examined the relationship between types of fat (visceral and subcutaneous) and brain volume.
For the new study, 10,000 healthy adults aged 20-80 years (mean age, 52.9 years; 53% men) underwent a short whole-body MRI protocol. Regression analyses of abdominal fat types and normalized brain volumes were evaluated, controlling for age and sex.
The research team found that higher amounts of both visceral and subcutaneous abdominal fat predicted lower total gray and white matter volume, as well as lower volume in the hippocampus, frontal cortex, and temporal, parietal, and occipital lobes.
“The findings are quite dramatic,” Dr. Raji told this news organization. “Overall, we found that both subcutaneous and visceral fat has similar levels of negative relationships with brain volumes.”
Women had a higher burden of brain atrophy with increased visceral fat than men. However, it’s difficult to place the sex differences in context because of the lack of prior work specifically investigating visceral fat, brain volume loss, and sex differences, the researchers caution.
They also note that while statistically significant relationships were observed between visceral fat levels and gray matter volume changes, their effect sizes were generally small.
“Thus, the statistical significance of this work is influenced by the large sample size and less so by large effect size in any given set of regions,” the investigators write.
Other limitations include the cross-sectional nature of the study, which precludes conclusions about causality. The analysis also did not account for other lifestyle factors such as physical activity, diet, and genetic variables.
The researchers call for further investigation “to better elucidate underlying mechanisms and discover possible interventions targeting abdominal fat reduction as a strategy to maintain brain health.”
‘Helpful addition to the literature’
In a comment, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, noted that “previous studies have linked obesity with cognitive decline and increased risk of dementia. Rather than using BMI as a proxy for body fat, the current study examined visceral and subcutaneous fat directly using imaging techniques.”
Dr. Sexton, who was not associated with this study, said the finding that increased body fat was associated with reduced brain volumes suggests “a possible mechanism to explain the previously reported associations between obesity and cognition.”
“Though some degree of atrophy and brain shrinkage is common with old age, awareness of this association is important because reduced brain volume may be associated with problems with thinking, memory, and performing everyday tasks, and because rates of obesity continue to rise in the United States, along with obesity-related conditions including heart disease, stroke, type 2 diabetes and certain types of cancer,” she added.
“While a helpful addition to the literature, the study does have important limitations. As an observational study, it cannot establish whether higher levels of body fat directly causes reduced brain volumes,” Dr. Sexton cautioned.
In addition, the study did not take into account important related factors like physical activity and diet, which may influence any relationship between body fat and brain volumes, she noted. “Overall, it is not just one factor that is important to consider when considering risk for cognitive decline and dementia, but multiple factors.
“Obesity and the location of body fat must be considered in combination with one’s total lived experience and habits, including physical activity, education, head injury, sleep, mental health, and the health of your heart/cardiovascular system and other key bodily systems,” Dr. Sexton said.
The Alzheimer’s Association is leading a 2-year clinical trial known as U.S. POINTER to see whether combining physical activity, healthy nutrition, social and intellectual challenges, and improved self-management of medical conditions can protect cognitive function in older adults who are at increased risk for cognitive decline.
This work was supported in part by Providence St. Joseph Health in Seattle; Saint John’s Health Center Foundation; Pacific Neuroscience Institute and Foundation; Will and Cary Singleton; and the McLoughlin family. Dr. Raji is a consultant for Brainreader, Apollo Health, Voxelwise, Neurevolution, Pacific Neuroscience Institute Foundation, and Icometrix. Dr. Sexton reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large study of healthy middle-aged adults, greater visceral and subcutaneous abdominal fat on abdominal MRI predicted brain atrophy on imaging, especially in women.
“The study shows that excess fat is bad for the brain and worse in women, including in Alzheimer’s disease risk regions,” lead author Cyrus Raji, MD, PhD, with the Mallinckrodt Institute of Radiology, Washington University, St. Louis, Mo., said in an interview.
The study was published online in the journal Aging and Disease
Modifiable risk factor
Multiple studies have suggested a connection between body fat accumulation and increased dementia risk. But few have examined the relationship between types of fat (visceral and subcutaneous) and brain volume.
For the new study, 10,000 healthy adults aged 20-80 years (mean age, 52.9 years; 53% men) underwent a short whole-body MRI protocol. Regression analyses of abdominal fat types and normalized brain volumes were evaluated, controlling for age and sex.
The research team found that higher amounts of both visceral and subcutaneous abdominal fat predicted lower total gray and white matter volume, as well as lower volume in the hippocampus, frontal cortex, and temporal, parietal, and occipital lobes.
“The findings are quite dramatic,” Dr. Raji told this news organization. “Overall, we found that both subcutaneous and visceral fat has similar levels of negative relationships with brain volumes.”
Women had a higher burden of brain atrophy with increased visceral fat than men. However, it’s difficult to place the sex differences in context because of the lack of prior work specifically investigating visceral fat, brain volume loss, and sex differences, the researchers caution.
They also note that while statistically significant relationships were observed between visceral fat levels and gray matter volume changes, their effect sizes were generally small.
“Thus, the statistical significance of this work is influenced by the large sample size and less so by large effect size in any given set of regions,” the investigators write.
Other limitations include the cross-sectional nature of the study, which precludes conclusions about causality. The analysis also did not account for other lifestyle factors such as physical activity, diet, and genetic variables.
The researchers call for further investigation “to better elucidate underlying mechanisms and discover possible interventions targeting abdominal fat reduction as a strategy to maintain brain health.”
‘Helpful addition to the literature’
In a comment, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, noted that “previous studies have linked obesity with cognitive decline and increased risk of dementia. Rather than using BMI as a proxy for body fat, the current study examined visceral and subcutaneous fat directly using imaging techniques.”
Dr. Sexton, who was not associated with this study, said the finding that increased body fat was associated with reduced brain volumes suggests “a possible mechanism to explain the previously reported associations between obesity and cognition.”
“Though some degree of atrophy and brain shrinkage is common with old age, awareness of this association is important because reduced brain volume may be associated with problems with thinking, memory, and performing everyday tasks, and because rates of obesity continue to rise in the United States, along with obesity-related conditions including heart disease, stroke, type 2 diabetes and certain types of cancer,” she added.
“While a helpful addition to the literature, the study does have important limitations. As an observational study, it cannot establish whether higher levels of body fat directly causes reduced brain volumes,” Dr. Sexton cautioned.
In addition, the study did not take into account important related factors like physical activity and diet, which may influence any relationship between body fat and brain volumes, she noted. “Overall, it is not just one factor that is important to consider when considering risk for cognitive decline and dementia, but multiple factors.
“Obesity and the location of body fat must be considered in combination with one’s total lived experience and habits, including physical activity, education, head injury, sleep, mental health, and the health of your heart/cardiovascular system and other key bodily systems,” Dr. Sexton said.
The Alzheimer’s Association is leading a 2-year clinical trial known as U.S. POINTER to see whether combining physical activity, healthy nutrition, social and intellectual challenges, and improved self-management of medical conditions can protect cognitive function in older adults who are at increased risk for cognitive decline.
This work was supported in part by Providence St. Joseph Health in Seattle; Saint John’s Health Center Foundation; Pacific Neuroscience Institute and Foundation; Will and Cary Singleton; and the McLoughlin family. Dr. Raji is a consultant for Brainreader, Apollo Health, Voxelwise, Neurevolution, Pacific Neuroscience Institute Foundation, and Icometrix. Dr. Sexton reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large study of healthy middle-aged adults, greater visceral and subcutaneous abdominal fat on abdominal MRI predicted brain atrophy on imaging, especially in women.
“The study shows that excess fat is bad for the brain and worse in women, including in Alzheimer’s disease risk regions,” lead author Cyrus Raji, MD, PhD, with the Mallinckrodt Institute of Radiology, Washington University, St. Louis, Mo., said in an interview.
The study was published online in the journal Aging and Disease
Modifiable risk factor
Multiple studies have suggested a connection between body fat accumulation and increased dementia risk. But few have examined the relationship between types of fat (visceral and subcutaneous) and brain volume.
For the new study, 10,000 healthy adults aged 20-80 years (mean age, 52.9 years; 53% men) underwent a short whole-body MRI protocol. Regression analyses of abdominal fat types and normalized brain volumes were evaluated, controlling for age and sex.
The research team found that higher amounts of both visceral and subcutaneous abdominal fat predicted lower total gray and white matter volume, as well as lower volume in the hippocampus, frontal cortex, and temporal, parietal, and occipital lobes.
“The findings are quite dramatic,” Dr. Raji told this news organization. “Overall, we found that both subcutaneous and visceral fat has similar levels of negative relationships with brain volumes.”
Women had a higher burden of brain atrophy with increased visceral fat than men. However, it’s difficult to place the sex differences in context because of the lack of prior work specifically investigating visceral fat, brain volume loss, and sex differences, the researchers caution.
They also note that while statistically significant relationships were observed between visceral fat levels and gray matter volume changes, their effect sizes were generally small.
“Thus, the statistical significance of this work is influenced by the large sample size and less so by large effect size in any given set of regions,” the investigators write.
Other limitations include the cross-sectional nature of the study, which precludes conclusions about causality. The analysis also did not account for other lifestyle factors such as physical activity, diet, and genetic variables.
The researchers call for further investigation “to better elucidate underlying mechanisms and discover possible interventions targeting abdominal fat reduction as a strategy to maintain brain health.”
‘Helpful addition to the literature’
In a comment, Claire Sexton, DPhil, Alzheimer’s Association senior director of scientific programs and outreach, noted that “previous studies have linked obesity with cognitive decline and increased risk of dementia. Rather than using BMI as a proxy for body fat, the current study examined visceral and subcutaneous fat directly using imaging techniques.”
Dr. Sexton, who was not associated with this study, said the finding that increased body fat was associated with reduced brain volumes suggests “a possible mechanism to explain the previously reported associations between obesity and cognition.”
“Though some degree of atrophy and brain shrinkage is common with old age, awareness of this association is important because reduced brain volume may be associated with problems with thinking, memory, and performing everyday tasks, and because rates of obesity continue to rise in the United States, along with obesity-related conditions including heart disease, stroke, type 2 diabetes and certain types of cancer,” she added.
“While a helpful addition to the literature, the study does have important limitations. As an observational study, it cannot establish whether higher levels of body fat directly causes reduced brain volumes,” Dr. Sexton cautioned.
In addition, the study did not take into account important related factors like physical activity and diet, which may influence any relationship between body fat and brain volumes, she noted. “Overall, it is not just one factor that is important to consider when considering risk for cognitive decline and dementia, but multiple factors.
“Obesity and the location of body fat must be considered in combination with one’s total lived experience and habits, including physical activity, education, head injury, sleep, mental health, and the health of your heart/cardiovascular system and other key bodily systems,” Dr. Sexton said.
The Alzheimer’s Association is leading a 2-year clinical trial known as U.S. POINTER to see whether combining physical activity, healthy nutrition, social and intellectual challenges, and improved self-management of medical conditions can protect cognitive function in older adults who are at increased risk for cognitive decline.
This work was supported in part by Providence St. Joseph Health in Seattle; Saint John’s Health Center Foundation; Pacific Neuroscience Institute and Foundation; Will and Cary Singleton; and the McLoughlin family. Dr. Raji is a consultant for Brainreader, Apollo Health, Voxelwise, Neurevolution, Pacific Neuroscience Institute Foundation, and Icometrix. Dr. Sexton reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AGING AND DISEASES
These four GI conditions may predict Parkinson’s disease
Early detection of these conditions might help identify patients at risk for PD, potentially prompting preventive strategies, the researchers suggest.
The results of previous experimental studies by the team supported the Braak hypothesis, which states that idiopathic PD originates in the gut in a subset of patients. However, no previous study had investigated a broad range of gastrointestinal symptoms and syndromes that might occur prior to a PD diagnosis.
Given their preclinical work, the authors were not surprised to find that certain GI syndromes were specifically associated with PD, even when compared with Alzheimer’s disease (AD) and cerebrovascular disease (CVD), principal author Pankaj Jay Pasricha, MBBS, MD, of Mayo Clinic Arizona, Scottsdale, said in an interview. However, they were “impressed by the strength of the associations.”
“Experts have known for a very long time that constipation is a potential risk factor for PD, so this study adds to the list of GI conditions that could potentially be risk factors,” he said.
The study was published online in Gut.
Studies converge
To determine the incidence of GI syndromes and interventions preceding PD, the investigators performed a combined case-control and cohort study using a U.S.-based nationwide medical record network.
First, they compared 24,624 individuals with new-onset idiopathic PD with the same number of matched negative controls (NCs), as well as 19,046 people with AD and 23,942 with CVD to investigate the presence of preexisting GI conditions, which the researchers referred to as “exposures.” Overall, the mean age was about 70, and about half of those studied were women.
Eighteen conditions covering the entire GI tract were investigated. These included achalasia, dysphagia, gastroesophageal reflux disease, gastroparesis, functional dyspepsia, paralytic ileus, diarrhea, irritable bowel syndrome (IBS) with and without diarrhea, intestinal pseudo-obstruction, fecal incontinence, Crohn’s disease, ulcerative colitis, and microscopic colitis, as well as appendectomy and vagotomy.
All GI syndromes were significantly increased in the PD group, compared with NCs (odds ratio > 1). However, only preexisting dysphagia (OR, 3.58), gastroparesis (OR, 4.64), functional dyspepsia (OR, 3.39), intestinal pseudo-obstruction (OR, 3.01), diarrhea (OR, 2.85), constipation (OR, 3.32), IBS with constipation (OR, 4.11), IBS with diarrhea (OR, 4.31), IBS without diarrhea (OR, 3.53), and fecal incontinence (OR, 3.76) produced ORs that were numerically greater than the upper limit of the negative exposures.
In addition, only gastroparesis, dysphagia, IBS with constipation, IBS without diarrhea, and constipation were specific for PD, compared with the AD and CVD groups (OR > 1). After correction for false discovery rate, though, gastroparesis and constipation did not remain significantly different, compared with the AD and CVD groups.
Other preexisting GI conditions not only were significantly associated with PD but also showed strong associations with the AD and CVD groups.
To validate the case-control analyses, the team set up a complementary cohort study. Eighteen cohorts – each diagnosed with one of the GI conditions in the case-control analysis – were compared with their respective NC cohorts for the prospective risk of developing PD, AD, or CVD within 5 years.
Gastroparesis, dysphagia, IBS without diarrhea, and constipation showed specific associations with PD versus NCs, AD, and CVD in the cohort analysis. Their relative risks versus NCs were 2.43, 2.27, 1.17, and 2.38, respectively.
Functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not PD specific, but IBS with constipation and intestinal pseudo-obstruction showed PD specificity in both the case-control (OR, 4.11) and cohort analyses (RR, 1.84).
Appendectomy decreased the risk for PD in the cohort analysis (RR, 0.48), but neither inflammatory bowel disease nor vagotomy was associated with PD.
“This study is the first to establish substantial observational evidence that the clinical diagnosis of not only constipation but also dysphagia, gastroparesis, and IBS without diarrhea might specifically predict the development of PD, whereas other exposures were less specific,” the researchers wrote.
However, Dr. Pasricha said, “there is no need for alarm.” Clinicians should reassure patients that “the overall risk for developing PD is low. The overwhelming majority of patients with these GI conditions will never develop PD.”
His team will be doing experimental work on the biological mechanisms that might explain the current study’s findings. “In addition, the U.S. National Institutes of Health has issued a call for proposals to perform research in patients that could help understand these associations better,” he said.
Body or brain?
The Parkinson’s Foundation’s National Medical Advisor, Michael S. Okun, MD, called the study “fascinating.”
The findings “confirm many other studies showing that GI symptoms can precede a Parkinson’s disease diagnosis,” he said in an interview.
Although the study was designed to test the Braak hypothesis, “the dataset really cannot confirm or refute Braak pathology, which can only be accomplished with comparison to postmortem samples,” he added.
“The raging debate in the field of body-first versus brain-first Parkinson’s may be somewhat artificial, especially if we consider that Parkinson’s is not one disease,” Dr. Okun noted. “It will take clinical data, pathology, and the collaboration of many researchers to solve the puzzle.”
“The Foundation continues to monitor all the advancements in the ‘gut’ Parkinson field,” he said. “We do not recommend at this time changing the approach to clinical care based on this data.”
No funding or competing interests were declared. Dr. Okun declared no relevant disclosures.
A version of this article first appeared on Medscape.com.
Early detection of these conditions might help identify patients at risk for PD, potentially prompting preventive strategies, the researchers suggest.
The results of previous experimental studies by the team supported the Braak hypothesis, which states that idiopathic PD originates in the gut in a subset of patients. However, no previous study had investigated a broad range of gastrointestinal symptoms and syndromes that might occur prior to a PD diagnosis.
Given their preclinical work, the authors were not surprised to find that certain GI syndromes were specifically associated with PD, even when compared with Alzheimer’s disease (AD) and cerebrovascular disease (CVD), principal author Pankaj Jay Pasricha, MBBS, MD, of Mayo Clinic Arizona, Scottsdale, said in an interview. However, they were “impressed by the strength of the associations.”
“Experts have known for a very long time that constipation is a potential risk factor for PD, so this study adds to the list of GI conditions that could potentially be risk factors,” he said.
The study was published online in Gut.
Studies converge
To determine the incidence of GI syndromes and interventions preceding PD, the investigators performed a combined case-control and cohort study using a U.S.-based nationwide medical record network.
First, they compared 24,624 individuals with new-onset idiopathic PD with the same number of matched negative controls (NCs), as well as 19,046 people with AD and 23,942 with CVD to investigate the presence of preexisting GI conditions, which the researchers referred to as “exposures.” Overall, the mean age was about 70, and about half of those studied were women.
Eighteen conditions covering the entire GI tract were investigated. These included achalasia, dysphagia, gastroesophageal reflux disease, gastroparesis, functional dyspepsia, paralytic ileus, diarrhea, irritable bowel syndrome (IBS) with and without diarrhea, intestinal pseudo-obstruction, fecal incontinence, Crohn’s disease, ulcerative colitis, and microscopic colitis, as well as appendectomy and vagotomy.
All GI syndromes were significantly increased in the PD group, compared with NCs (odds ratio > 1). However, only preexisting dysphagia (OR, 3.58), gastroparesis (OR, 4.64), functional dyspepsia (OR, 3.39), intestinal pseudo-obstruction (OR, 3.01), diarrhea (OR, 2.85), constipation (OR, 3.32), IBS with constipation (OR, 4.11), IBS with diarrhea (OR, 4.31), IBS without diarrhea (OR, 3.53), and fecal incontinence (OR, 3.76) produced ORs that were numerically greater than the upper limit of the negative exposures.
In addition, only gastroparesis, dysphagia, IBS with constipation, IBS without diarrhea, and constipation were specific for PD, compared with the AD and CVD groups (OR > 1). After correction for false discovery rate, though, gastroparesis and constipation did not remain significantly different, compared with the AD and CVD groups.
Other preexisting GI conditions not only were significantly associated with PD but also showed strong associations with the AD and CVD groups.
To validate the case-control analyses, the team set up a complementary cohort study. Eighteen cohorts – each diagnosed with one of the GI conditions in the case-control analysis – were compared with their respective NC cohorts for the prospective risk of developing PD, AD, or CVD within 5 years.
Gastroparesis, dysphagia, IBS without diarrhea, and constipation showed specific associations with PD versus NCs, AD, and CVD in the cohort analysis. Their relative risks versus NCs were 2.43, 2.27, 1.17, and 2.38, respectively.
Functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not PD specific, but IBS with constipation and intestinal pseudo-obstruction showed PD specificity in both the case-control (OR, 4.11) and cohort analyses (RR, 1.84).
Appendectomy decreased the risk for PD in the cohort analysis (RR, 0.48), but neither inflammatory bowel disease nor vagotomy was associated with PD.
“This study is the first to establish substantial observational evidence that the clinical diagnosis of not only constipation but also dysphagia, gastroparesis, and IBS without diarrhea might specifically predict the development of PD, whereas other exposures were less specific,” the researchers wrote.
However, Dr. Pasricha said, “there is no need for alarm.” Clinicians should reassure patients that “the overall risk for developing PD is low. The overwhelming majority of patients with these GI conditions will never develop PD.”
His team will be doing experimental work on the biological mechanisms that might explain the current study’s findings. “In addition, the U.S. National Institutes of Health has issued a call for proposals to perform research in patients that could help understand these associations better,” he said.
Body or brain?
The Parkinson’s Foundation’s National Medical Advisor, Michael S. Okun, MD, called the study “fascinating.”
The findings “confirm many other studies showing that GI symptoms can precede a Parkinson’s disease diagnosis,” he said in an interview.
Although the study was designed to test the Braak hypothesis, “the dataset really cannot confirm or refute Braak pathology, which can only be accomplished with comparison to postmortem samples,” he added.
“The raging debate in the field of body-first versus brain-first Parkinson’s may be somewhat artificial, especially if we consider that Parkinson’s is not one disease,” Dr. Okun noted. “It will take clinical data, pathology, and the collaboration of many researchers to solve the puzzle.”
“The Foundation continues to monitor all the advancements in the ‘gut’ Parkinson field,” he said. “We do not recommend at this time changing the approach to clinical care based on this data.”
No funding or competing interests were declared. Dr. Okun declared no relevant disclosures.
A version of this article first appeared on Medscape.com.
Early detection of these conditions might help identify patients at risk for PD, potentially prompting preventive strategies, the researchers suggest.
The results of previous experimental studies by the team supported the Braak hypothesis, which states that idiopathic PD originates in the gut in a subset of patients. However, no previous study had investigated a broad range of gastrointestinal symptoms and syndromes that might occur prior to a PD diagnosis.
Given their preclinical work, the authors were not surprised to find that certain GI syndromes were specifically associated with PD, even when compared with Alzheimer’s disease (AD) and cerebrovascular disease (CVD), principal author Pankaj Jay Pasricha, MBBS, MD, of Mayo Clinic Arizona, Scottsdale, said in an interview. However, they were “impressed by the strength of the associations.”
“Experts have known for a very long time that constipation is a potential risk factor for PD, so this study adds to the list of GI conditions that could potentially be risk factors,” he said.
The study was published online in Gut.
Studies converge
To determine the incidence of GI syndromes and interventions preceding PD, the investigators performed a combined case-control and cohort study using a U.S.-based nationwide medical record network.
First, they compared 24,624 individuals with new-onset idiopathic PD with the same number of matched negative controls (NCs), as well as 19,046 people with AD and 23,942 with CVD to investigate the presence of preexisting GI conditions, which the researchers referred to as “exposures.” Overall, the mean age was about 70, and about half of those studied were women.
Eighteen conditions covering the entire GI tract were investigated. These included achalasia, dysphagia, gastroesophageal reflux disease, gastroparesis, functional dyspepsia, paralytic ileus, diarrhea, irritable bowel syndrome (IBS) with and without diarrhea, intestinal pseudo-obstruction, fecal incontinence, Crohn’s disease, ulcerative colitis, and microscopic colitis, as well as appendectomy and vagotomy.
All GI syndromes were significantly increased in the PD group, compared with NCs (odds ratio > 1). However, only preexisting dysphagia (OR, 3.58), gastroparesis (OR, 4.64), functional dyspepsia (OR, 3.39), intestinal pseudo-obstruction (OR, 3.01), diarrhea (OR, 2.85), constipation (OR, 3.32), IBS with constipation (OR, 4.11), IBS with diarrhea (OR, 4.31), IBS without diarrhea (OR, 3.53), and fecal incontinence (OR, 3.76) produced ORs that were numerically greater than the upper limit of the negative exposures.
In addition, only gastroparesis, dysphagia, IBS with constipation, IBS without diarrhea, and constipation were specific for PD, compared with the AD and CVD groups (OR > 1). After correction for false discovery rate, though, gastroparesis and constipation did not remain significantly different, compared with the AD and CVD groups.
Other preexisting GI conditions not only were significantly associated with PD but also showed strong associations with the AD and CVD groups.
To validate the case-control analyses, the team set up a complementary cohort study. Eighteen cohorts – each diagnosed with one of the GI conditions in the case-control analysis – were compared with their respective NC cohorts for the prospective risk of developing PD, AD, or CVD within 5 years.
Gastroparesis, dysphagia, IBS without diarrhea, and constipation showed specific associations with PD versus NCs, AD, and CVD in the cohort analysis. Their relative risks versus NCs were 2.43, 2.27, 1.17, and 2.38, respectively.
Functional dyspepsia, IBS with diarrhea, diarrhea, and fecal incontinence were not PD specific, but IBS with constipation and intestinal pseudo-obstruction showed PD specificity in both the case-control (OR, 4.11) and cohort analyses (RR, 1.84).
Appendectomy decreased the risk for PD in the cohort analysis (RR, 0.48), but neither inflammatory bowel disease nor vagotomy was associated with PD.
“This study is the first to establish substantial observational evidence that the clinical diagnosis of not only constipation but also dysphagia, gastroparesis, and IBS without diarrhea might specifically predict the development of PD, whereas other exposures were less specific,” the researchers wrote.
However, Dr. Pasricha said, “there is no need for alarm.” Clinicians should reassure patients that “the overall risk for developing PD is low. The overwhelming majority of patients with these GI conditions will never develop PD.”
His team will be doing experimental work on the biological mechanisms that might explain the current study’s findings. “In addition, the U.S. National Institutes of Health has issued a call for proposals to perform research in patients that could help understand these associations better,” he said.
Body or brain?
The Parkinson’s Foundation’s National Medical Advisor, Michael S. Okun, MD, called the study “fascinating.”
The findings “confirm many other studies showing that GI symptoms can precede a Parkinson’s disease diagnosis,” he said in an interview.
Although the study was designed to test the Braak hypothesis, “the dataset really cannot confirm or refute Braak pathology, which can only be accomplished with comparison to postmortem samples,” he added.
“The raging debate in the field of body-first versus brain-first Parkinson’s may be somewhat artificial, especially if we consider that Parkinson’s is not one disease,” Dr. Okun noted. “It will take clinical data, pathology, and the collaboration of many researchers to solve the puzzle.”
“The Foundation continues to monitor all the advancements in the ‘gut’ Parkinson field,” he said. “We do not recommend at this time changing the approach to clinical care based on this data.”
No funding or competing interests were declared. Dr. Okun declared no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM GUT
Even an hour’s walk a week lowers risk in type 2 diabetes
although the impact on retinopathy is weaker, reveals a cohort study of U.K. individuals.
The research, based on data from more than 18,000 participants in the U.K. Biobank, suggests that the minimal level of self-reported activity to reduce the risk for both neuropathy and nephropathy may be the equivalent of less than 1.5 hours of walking per week.
The results are “encouraging and reassuring for both physicians and patients,” lead author Frederik P.B. Kristensen, MSc, PhD student, department of clinical epidemiology, Aarhus (Denmark) University, said in an interview.
“Our findings are particularly promising for neuropathy since, currently, no disease-modifying treatment exists, and there are limited preventive strategies available.”
Mr. Kristensen highlighted that “most diabetes research has focused on all-cause mortality and macrovascular complications. In the current study, we also found the same pattern for microvascular complications: Even small amounts of physical activity will benefit your health status.”
The minimal level of activity they identified, he said, is also an “achievable [goal] for most type 2 diabetes patients.”
Mr. Kristensen added, however, that the study was limited by excluding individuals with limited mobility and those living in temporary accommodation or care homes.
And prospective studies are required to determine the dose-response relationship between total, not just leisure-time, activity – ideally measured objectively – and risk for microvascular complications, he observed.
The research was published recently in Diabetes Care.
Impact of exercise on microvascular complications in T2D has been uncertain
The authors point out that microvascular complications – such as nerve damage (neuropathy), kidney problems (nephropathy), and eye complications (retinopathy) – occur in more than 50% of individuals with type 2 diabetes and have a “substantial impact” on quality of life, on top of the impact of macrovascular complications (such as cardiovascular disease), disability, and mortality.
Although physical activity is seen as a “cornerstone in the multifactorial management of type 2 diabetes because of its beneficial effects on metabolic risk factors,” the impact on microvascular complications is “uncertain” and the evidence is limited and “conflicting.”
The researchers therefore sought to examine the dose-response association, including the minimal effective level, between leisure-time physical activity and neuropathy, nephropathy, and retinopathy.
They conducted a cohort study of individuals aged 37-82 years from the U.K. Biobank who had type 2 diabetes, which was identified using the Eastwood algorithm and/or an A1c greater than or equal to 48 mmol/mol (6.5%).
Individuals with type 1 diabetes or gestational diabetes were excluded, as were those with major disabling somatic disorders, neurodegenerative diseases, and mental disorders, among others.
Leisure-time physical activity was based on the self-reported frequency, duration, and types of physical activities and was combined to calculate the total leisure time activity in MET-hours per week.
Using the American Diabetes Association/World Health Organization recommendations of 150-300 minutes of moderate to vigorous leisure-time physical activity per week, the researchers determined the recommended moderate activity level to be 150 minutes, (equivalent to 2.5 hours, or 7.5 MET-hours per week).
In all, 18,092 individuals with type 2 diabetes were included in the analysis, of whom 37% were women. The mean age was 60 years.
Ten percent of participants performed no leisure-time physical activity, 38% performed activity below the threshold for moderate activity, 20% performed at the recommended level, and 32% were more active.
Those performing no physical activity were more likely to be women, to be younger, to have a higher body mass index, and to have a greater average A1c, as well as have a more unfavorable sociodemographic and behavioral profile.
Over a median follow-up of 12.1 years, 3.7% of the participants were diagnosed with neuropathy, 10.2% with nephropathy, and 11.7% with retinopathy, equating to an incidence per 1,000 person-years of 3.5, 9,8, and 11.4, respectively.
The researchers found that any level of physical activity was associated with an approximate reduction in the risk for neuropathy and nephropathy.
Multivariate analysis indicated that, compared with no physical activity, activity below the recommended level was associated with an adjusted hazard ratio (aHR) for neuropathy of 0.71, whereas the aHR for activity at the recommended level was 0.73 and that for activity above the recommended level was 0.67.
The aHR for nephropathy, compared with no physical activity, was 0.79 for activity below the recommended level, 0.80 for activity at the recommended level, and 0.80 for activity above the recommended level.
The association between physical activity and retinopathy was weaker, however, at aHRs of 0.91, 0.91, and 0.98 for activity below, at, and above the recommended level, respectively.
The researchers suggest that this lower association could be due to differences in the etiology of the different forms of microvascular complications.
Hyperglycemia is the key driver in the development of retinopathy, they note, whereas other metabolic risk factors, such as obesity, insulin resistance, inflammation, dyslipidemia, and hypertension, play a role in neuropathy and nephropathy.
The associations were also less pronounced in women.
Mr. Kristensen said that this is “an important area that needs to be addressed.”
“While different rates between men and women regarding incidence of type 2 diabetes, metabolic risk factors, complications, and the initiation of, and adherence to, therapy have been found,” he continued, “the exact mechanisms remain unclear. We need a further understanding of sex-differences in metabolic regulation, as well as in material living conditions, social and psychological factors, and access to health care, which may influence the risk of complications.”
Mr. Kristensen added, “Sex differences may be present in more areas than we are aware.”
Mr. Kristensen is supported by a PhD grant from Aarhus University. Other authors received funding from the Danish Diabetes Association, the Australian National Health and Medical Research Council, the New South Wales Government, the Spanish Ministry of Universities, the European Union NextGenerationEU/PRTR (Plan de Recuperación) through a Margarita Salas contract of the University of Vigo, and the Government of Andalusia, Research Talent Recruitment Programme. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
although the impact on retinopathy is weaker, reveals a cohort study of U.K. individuals.
The research, based on data from more than 18,000 participants in the U.K. Biobank, suggests that the minimal level of self-reported activity to reduce the risk for both neuropathy and nephropathy may be the equivalent of less than 1.5 hours of walking per week.
The results are “encouraging and reassuring for both physicians and patients,” lead author Frederik P.B. Kristensen, MSc, PhD student, department of clinical epidemiology, Aarhus (Denmark) University, said in an interview.
“Our findings are particularly promising for neuropathy since, currently, no disease-modifying treatment exists, and there are limited preventive strategies available.”
Mr. Kristensen highlighted that “most diabetes research has focused on all-cause mortality and macrovascular complications. In the current study, we also found the same pattern for microvascular complications: Even small amounts of physical activity will benefit your health status.”
The minimal level of activity they identified, he said, is also an “achievable [goal] for most type 2 diabetes patients.”
Mr. Kristensen added, however, that the study was limited by excluding individuals with limited mobility and those living in temporary accommodation or care homes.
And prospective studies are required to determine the dose-response relationship between total, not just leisure-time, activity – ideally measured objectively – and risk for microvascular complications, he observed.
The research was published recently in Diabetes Care.
Impact of exercise on microvascular complications in T2D has been uncertain
The authors point out that microvascular complications – such as nerve damage (neuropathy), kidney problems (nephropathy), and eye complications (retinopathy) – occur in more than 50% of individuals with type 2 diabetes and have a “substantial impact” on quality of life, on top of the impact of macrovascular complications (such as cardiovascular disease), disability, and mortality.
Although physical activity is seen as a “cornerstone in the multifactorial management of type 2 diabetes because of its beneficial effects on metabolic risk factors,” the impact on microvascular complications is “uncertain” and the evidence is limited and “conflicting.”
The researchers therefore sought to examine the dose-response association, including the minimal effective level, between leisure-time physical activity and neuropathy, nephropathy, and retinopathy.
They conducted a cohort study of individuals aged 37-82 years from the U.K. Biobank who had type 2 diabetes, which was identified using the Eastwood algorithm and/or an A1c greater than or equal to 48 mmol/mol (6.5%).
Individuals with type 1 diabetes or gestational diabetes were excluded, as were those with major disabling somatic disorders, neurodegenerative diseases, and mental disorders, among others.
Leisure-time physical activity was based on the self-reported frequency, duration, and types of physical activities and was combined to calculate the total leisure time activity in MET-hours per week.
Using the American Diabetes Association/World Health Organization recommendations of 150-300 minutes of moderate to vigorous leisure-time physical activity per week, the researchers determined the recommended moderate activity level to be 150 minutes, (equivalent to 2.5 hours, or 7.5 MET-hours per week).
In all, 18,092 individuals with type 2 diabetes were included in the analysis, of whom 37% were women. The mean age was 60 years.
Ten percent of participants performed no leisure-time physical activity, 38% performed activity below the threshold for moderate activity, 20% performed at the recommended level, and 32% were more active.
Those performing no physical activity were more likely to be women, to be younger, to have a higher body mass index, and to have a greater average A1c, as well as have a more unfavorable sociodemographic and behavioral profile.
Over a median follow-up of 12.1 years, 3.7% of the participants were diagnosed with neuropathy, 10.2% with nephropathy, and 11.7% with retinopathy, equating to an incidence per 1,000 person-years of 3.5, 9,8, and 11.4, respectively.
The researchers found that any level of physical activity was associated with an approximate reduction in the risk for neuropathy and nephropathy.
Multivariate analysis indicated that, compared with no physical activity, activity below the recommended level was associated with an adjusted hazard ratio (aHR) for neuropathy of 0.71, whereas the aHR for activity at the recommended level was 0.73 and that for activity above the recommended level was 0.67.
The aHR for nephropathy, compared with no physical activity, was 0.79 for activity below the recommended level, 0.80 for activity at the recommended level, and 0.80 for activity above the recommended level.
The association between physical activity and retinopathy was weaker, however, at aHRs of 0.91, 0.91, and 0.98 for activity below, at, and above the recommended level, respectively.
The researchers suggest that this lower association could be due to differences in the etiology of the different forms of microvascular complications.
Hyperglycemia is the key driver in the development of retinopathy, they note, whereas other metabolic risk factors, such as obesity, insulin resistance, inflammation, dyslipidemia, and hypertension, play a role in neuropathy and nephropathy.
The associations were also less pronounced in women.
Mr. Kristensen said that this is “an important area that needs to be addressed.”
“While different rates between men and women regarding incidence of type 2 diabetes, metabolic risk factors, complications, and the initiation of, and adherence to, therapy have been found,” he continued, “the exact mechanisms remain unclear. We need a further understanding of sex-differences in metabolic regulation, as well as in material living conditions, social and psychological factors, and access to health care, which may influence the risk of complications.”
Mr. Kristensen added, “Sex differences may be present in more areas than we are aware.”
Mr. Kristensen is supported by a PhD grant from Aarhus University. Other authors received funding from the Danish Diabetes Association, the Australian National Health and Medical Research Council, the New South Wales Government, the Spanish Ministry of Universities, the European Union NextGenerationEU/PRTR (Plan de Recuperación) through a Margarita Salas contract of the University of Vigo, and the Government of Andalusia, Research Talent Recruitment Programme. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
although the impact on retinopathy is weaker, reveals a cohort study of U.K. individuals.
The research, based on data from more than 18,000 participants in the U.K. Biobank, suggests that the minimal level of self-reported activity to reduce the risk for both neuropathy and nephropathy may be the equivalent of less than 1.5 hours of walking per week.
The results are “encouraging and reassuring for both physicians and patients,” lead author Frederik P.B. Kristensen, MSc, PhD student, department of clinical epidemiology, Aarhus (Denmark) University, said in an interview.
“Our findings are particularly promising for neuropathy since, currently, no disease-modifying treatment exists, and there are limited preventive strategies available.”
Mr. Kristensen highlighted that “most diabetes research has focused on all-cause mortality and macrovascular complications. In the current study, we also found the same pattern for microvascular complications: Even small amounts of physical activity will benefit your health status.”
The minimal level of activity they identified, he said, is also an “achievable [goal] for most type 2 diabetes patients.”
Mr. Kristensen added, however, that the study was limited by excluding individuals with limited mobility and those living in temporary accommodation or care homes.
And prospective studies are required to determine the dose-response relationship between total, not just leisure-time, activity – ideally measured objectively – and risk for microvascular complications, he observed.
The research was published recently in Diabetes Care.
Impact of exercise on microvascular complications in T2D has been uncertain
The authors point out that microvascular complications – such as nerve damage (neuropathy), kidney problems (nephropathy), and eye complications (retinopathy) – occur in more than 50% of individuals with type 2 diabetes and have a “substantial impact” on quality of life, on top of the impact of macrovascular complications (such as cardiovascular disease), disability, and mortality.
Although physical activity is seen as a “cornerstone in the multifactorial management of type 2 diabetes because of its beneficial effects on metabolic risk factors,” the impact on microvascular complications is “uncertain” and the evidence is limited and “conflicting.”
The researchers therefore sought to examine the dose-response association, including the minimal effective level, between leisure-time physical activity and neuropathy, nephropathy, and retinopathy.
They conducted a cohort study of individuals aged 37-82 years from the U.K. Biobank who had type 2 diabetes, which was identified using the Eastwood algorithm and/or an A1c greater than or equal to 48 mmol/mol (6.5%).
Individuals with type 1 diabetes or gestational diabetes were excluded, as were those with major disabling somatic disorders, neurodegenerative diseases, and mental disorders, among others.
Leisure-time physical activity was based on the self-reported frequency, duration, and types of physical activities and was combined to calculate the total leisure time activity in MET-hours per week.
Using the American Diabetes Association/World Health Organization recommendations of 150-300 minutes of moderate to vigorous leisure-time physical activity per week, the researchers determined the recommended moderate activity level to be 150 minutes, (equivalent to 2.5 hours, or 7.5 MET-hours per week).
In all, 18,092 individuals with type 2 diabetes were included in the analysis, of whom 37% were women. The mean age was 60 years.
Ten percent of participants performed no leisure-time physical activity, 38% performed activity below the threshold for moderate activity, 20% performed at the recommended level, and 32% were more active.
Those performing no physical activity were more likely to be women, to be younger, to have a higher body mass index, and to have a greater average A1c, as well as have a more unfavorable sociodemographic and behavioral profile.
Over a median follow-up of 12.1 years, 3.7% of the participants were diagnosed with neuropathy, 10.2% with nephropathy, and 11.7% with retinopathy, equating to an incidence per 1,000 person-years of 3.5, 9,8, and 11.4, respectively.
The researchers found that any level of physical activity was associated with an approximate reduction in the risk for neuropathy and nephropathy.
Multivariate analysis indicated that, compared with no physical activity, activity below the recommended level was associated with an adjusted hazard ratio (aHR) for neuropathy of 0.71, whereas the aHR for activity at the recommended level was 0.73 and that for activity above the recommended level was 0.67.
The aHR for nephropathy, compared with no physical activity, was 0.79 for activity below the recommended level, 0.80 for activity at the recommended level, and 0.80 for activity above the recommended level.
The association between physical activity and retinopathy was weaker, however, at aHRs of 0.91, 0.91, and 0.98 for activity below, at, and above the recommended level, respectively.
The researchers suggest that this lower association could be due to differences in the etiology of the different forms of microvascular complications.
Hyperglycemia is the key driver in the development of retinopathy, they note, whereas other metabolic risk factors, such as obesity, insulin resistance, inflammation, dyslipidemia, and hypertension, play a role in neuropathy and nephropathy.
The associations were also less pronounced in women.
Mr. Kristensen said that this is “an important area that needs to be addressed.”
“While different rates between men and women regarding incidence of type 2 diabetes, metabolic risk factors, complications, and the initiation of, and adherence to, therapy have been found,” he continued, “the exact mechanisms remain unclear. We need a further understanding of sex-differences in metabolic regulation, as well as in material living conditions, social and psychological factors, and access to health care, which may influence the risk of complications.”
Mr. Kristensen added, “Sex differences may be present in more areas than we are aware.”
Mr. Kristensen is supported by a PhD grant from Aarhus University. Other authors received funding from the Danish Diabetes Association, the Australian National Health and Medical Research Council, the New South Wales Government, the Spanish Ministry of Universities, the European Union NextGenerationEU/PRTR (Plan de Recuperación) through a Margarita Salas contract of the University of Vigo, and the Government of Andalusia, Research Talent Recruitment Programme. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
FROM DIABETES CARE
CTE common among young athletes in largest brain donor study
Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.
Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.
“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.
The findings were published online in JAMA Neurology.
A rare look
Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.
“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.
The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.
Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.
Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.
CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke.
More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).
Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).
The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.
“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
Early stage of CTE?
Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.
Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.
“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.
Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.
“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
A message for clinicians
All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.
While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.
For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.
“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.
The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.
A version of this article appeared on Medscape.com.
Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.
Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.
“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.
The findings were published online in JAMA Neurology.
A rare look
Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.
“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.
The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.
Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.
Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.
CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke.
More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).
Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).
The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.
“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
Early stage of CTE?
Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.
Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.
“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.
Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.
“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
A message for clinicians
All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.
While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.
For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.
“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.
The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.
A version of this article appeared on Medscape.com.
Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.
Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.
“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.
The findings were published online in JAMA Neurology.
A rare look
Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.
“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.
The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.
Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.
Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.
CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke.
More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).
Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).
The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.
“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
Early stage of CTE?
Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.
Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.
“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.
Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.
“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
A message for clinicians
All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.
While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.
For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.
“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.
The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.
A version of this article appeared on Medscape.com.
Number of people with long COVID could be vastly underestimated
It’s been estimated that up to one-third of people who survive acute SARS-CoV-2 infection will suffer a post-viral syndrome with lingering neurologic and other symptoms – now known as long COVID or neurological postacute sequelae of SARS-CoV-2 infection (Neuro-PASC).
However, Researchers found a significant proportion of patients in their small study who had never tested positive for COVID-19 but who were having symptoms of long COVID nevertheless showed evidence of immune responses consistent with previous exposure.
“We estimate that millions of people got COVID in the U.S. during the first year of the pandemic and then developed long COVID, yet they did not get a positive COVID diagnosis because of testing limitations,” Igor J. Koralnik, MD, of Northwestern Medicine Comprehensive COVID-19 Center in Chicago, said in an interview.
He noted that many post-COVID-19 clinics in the United States don’t accept people with long COVID symptoms who do not have a positive test result.
Patients with long COVID symptoms but without laboratory evidence of prior infection, “who have often been rejected and stigmatized, should feel vindicated by the results of our study,” Dr. Koralnik said.
“We think that those patients deserve the same clinical care as those with a positive test, as well as inclusion in research studies. This is what we are doing at Northwestern Medicine’s Comprehensive COVID[-19] Center,” Dr. Koralnik added.
The study was published online in the journal Neurology: Neuroimmunology & Neuroinflammation.
Delayed care
The researchers measured SARS-CoV-2-specific humoral and cell-mediated immune responses against nucleocapsid protein and spike proteins, which indicate a prior COVID-19 infection, in 29 patients with post-viral syndrome after suspected COVID-19, including neurologic symptoms such as cognitive impairment, headache, and fatigue, but who did not have a confirmed positive COVID-19 test.
They did the same in 32 age- and sex-matched COVID long haulers with confirmed Neuro-PASC and 18 healthy controls with none of the symptoms of long COVID and no known exposure to SARS-CoV-2 or positive test result.
They found that 12 of the 29 patients (41%) with post-viral syndrome (but no positive COVID-19 test) had detectable humoral and cellular immune responses consistent with prior exposure to SARS-CoV-2. Three-quarters harbored antinucleocapsid and 50% harbored antispike responses.
“Our data suggest that at least 4 million people with post-viral syndrome similar to long COVID may indeed have detectable immune responses to support a COVID diagnosis,” Dr. Koralnik said in a news release.
The 12 patients with post-viral syndrome but without a confirmed COVID-19 test had neurologic symptoms similar to those of patients with confirmed Neuro-PASC.
However, lack of a confirmed COVID-19 diagnosis likely contributed to the 5-month delay in the median time from symptom onset to clinic visit, the researchers said. They were evaluated at a median of 10.7 months vs. 5.4 months for Neuro-PASC patients.
Dr. Koralnik said in an interview that the “most important take-home message” of the study is that patients with post-viral syndrome often present with clinical manifestations similar to those of confirmed patients with Neuro-PASC, suggesting that a positive result by commercially available SARS-CoV-2 diagnostic test should not be a prerequisite for accessing care.
Patients with post-viral syndrome may benefit from the same clinical care as confirmed patients with Neuro-PASC, and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment, he added.
A version of this article first appeared on Medscape.com .
This article was updated 8/28/23.
It’s been estimated that up to one-third of people who survive acute SARS-CoV-2 infection will suffer a post-viral syndrome with lingering neurologic and other symptoms – now known as long COVID or neurological postacute sequelae of SARS-CoV-2 infection (Neuro-PASC).
However, Researchers found a significant proportion of patients in their small study who had never tested positive for COVID-19 but who were having symptoms of long COVID nevertheless showed evidence of immune responses consistent with previous exposure.
“We estimate that millions of people got COVID in the U.S. during the first year of the pandemic and then developed long COVID, yet they did not get a positive COVID diagnosis because of testing limitations,” Igor J. Koralnik, MD, of Northwestern Medicine Comprehensive COVID-19 Center in Chicago, said in an interview.
He noted that many post-COVID-19 clinics in the United States don’t accept people with long COVID symptoms who do not have a positive test result.
Patients with long COVID symptoms but without laboratory evidence of prior infection, “who have often been rejected and stigmatized, should feel vindicated by the results of our study,” Dr. Koralnik said.
“We think that those patients deserve the same clinical care as those with a positive test, as well as inclusion in research studies. This is what we are doing at Northwestern Medicine’s Comprehensive COVID[-19] Center,” Dr. Koralnik added.
The study was published online in the journal Neurology: Neuroimmunology & Neuroinflammation.
Delayed care
The researchers measured SARS-CoV-2-specific humoral and cell-mediated immune responses against nucleocapsid protein and spike proteins, which indicate a prior COVID-19 infection, in 29 patients with post-viral syndrome after suspected COVID-19, including neurologic symptoms such as cognitive impairment, headache, and fatigue, but who did not have a confirmed positive COVID-19 test.
They did the same in 32 age- and sex-matched COVID long haulers with confirmed Neuro-PASC and 18 healthy controls with none of the symptoms of long COVID and no known exposure to SARS-CoV-2 or positive test result.
They found that 12 of the 29 patients (41%) with post-viral syndrome (but no positive COVID-19 test) had detectable humoral and cellular immune responses consistent with prior exposure to SARS-CoV-2. Three-quarters harbored antinucleocapsid and 50% harbored antispike responses.
“Our data suggest that at least 4 million people with post-viral syndrome similar to long COVID may indeed have detectable immune responses to support a COVID diagnosis,” Dr. Koralnik said in a news release.
The 12 patients with post-viral syndrome but without a confirmed COVID-19 test had neurologic symptoms similar to those of patients with confirmed Neuro-PASC.
However, lack of a confirmed COVID-19 diagnosis likely contributed to the 5-month delay in the median time from symptom onset to clinic visit, the researchers said. They were evaluated at a median of 10.7 months vs. 5.4 months for Neuro-PASC patients.
Dr. Koralnik said in an interview that the “most important take-home message” of the study is that patients with post-viral syndrome often present with clinical manifestations similar to those of confirmed patients with Neuro-PASC, suggesting that a positive result by commercially available SARS-CoV-2 diagnostic test should not be a prerequisite for accessing care.
Patients with post-viral syndrome may benefit from the same clinical care as confirmed patients with Neuro-PASC, and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment, he added.
A version of this article first appeared on Medscape.com .
This article was updated 8/28/23.
It’s been estimated that up to one-third of people who survive acute SARS-CoV-2 infection will suffer a post-viral syndrome with lingering neurologic and other symptoms – now known as long COVID or neurological postacute sequelae of SARS-CoV-2 infection (Neuro-PASC).
However, Researchers found a significant proportion of patients in their small study who had never tested positive for COVID-19 but who were having symptoms of long COVID nevertheless showed evidence of immune responses consistent with previous exposure.
“We estimate that millions of people got COVID in the U.S. during the first year of the pandemic and then developed long COVID, yet they did not get a positive COVID diagnosis because of testing limitations,” Igor J. Koralnik, MD, of Northwestern Medicine Comprehensive COVID-19 Center in Chicago, said in an interview.
He noted that many post-COVID-19 clinics in the United States don’t accept people with long COVID symptoms who do not have a positive test result.
Patients with long COVID symptoms but without laboratory evidence of prior infection, “who have often been rejected and stigmatized, should feel vindicated by the results of our study,” Dr. Koralnik said.
“We think that those patients deserve the same clinical care as those with a positive test, as well as inclusion in research studies. This is what we are doing at Northwestern Medicine’s Comprehensive COVID[-19] Center,” Dr. Koralnik added.
The study was published online in the journal Neurology: Neuroimmunology & Neuroinflammation.
Delayed care
The researchers measured SARS-CoV-2-specific humoral and cell-mediated immune responses against nucleocapsid protein and spike proteins, which indicate a prior COVID-19 infection, in 29 patients with post-viral syndrome after suspected COVID-19, including neurologic symptoms such as cognitive impairment, headache, and fatigue, but who did not have a confirmed positive COVID-19 test.
They did the same in 32 age- and sex-matched COVID long haulers with confirmed Neuro-PASC and 18 healthy controls with none of the symptoms of long COVID and no known exposure to SARS-CoV-2 or positive test result.
They found that 12 of the 29 patients (41%) with post-viral syndrome (but no positive COVID-19 test) had detectable humoral and cellular immune responses consistent with prior exposure to SARS-CoV-2. Three-quarters harbored antinucleocapsid and 50% harbored antispike responses.
“Our data suggest that at least 4 million people with post-viral syndrome similar to long COVID may indeed have detectable immune responses to support a COVID diagnosis,” Dr. Koralnik said in a news release.
The 12 patients with post-viral syndrome but without a confirmed COVID-19 test had neurologic symptoms similar to those of patients with confirmed Neuro-PASC.
However, lack of a confirmed COVID-19 diagnosis likely contributed to the 5-month delay in the median time from symptom onset to clinic visit, the researchers said. They were evaluated at a median of 10.7 months vs. 5.4 months for Neuro-PASC patients.
Dr. Koralnik said in an interview that the “most important take-home message” of the study is that patients with post-viral syndrome often present with clinical manifestations similar to those of confirmed patients with Neuro-PASC, suggesting that a positive result by commercially available SARS-CoV-2 diagnostic test should not be a prerequisite for accessing care.
Patients with post-viral syndrome may benefit from the same clinical care as confirmed patients with Neuro-PASC, and the absence of a positive SARS-CoV-2 test should not preclude or delay treatment, he added.
A version of this article first appeared on Medscape.com .
This article was updated 8/28/23.
FROM NEUROLOGY, NEUROIMMUNOLOGY & NEUROINFLAMMATION
Liraglutide fixes learning limit tied to insulin resistance
A single injection of the GLP-1 receptor agonist liraglutide led to short-term normalization of associative learning in people with obesity and insulin resistance, a finding that suggests say the authors of a recent report in Nature Metabolism.
“We demonstrated that dopamine-driven associative learning about external sensory cues crucially depends on metabolic signaling,” said Marc Tittgemeyer, PhD, professor at the Max Planck Institute for Metabolism Research in Cologne, Germany, and senior author of the study. Study participants with impaired insulin sensitivity “exhibited a reduced amplitude of behavioral updating that was normalized” by a single subcutaneous injection of 0.6 mg of liraglutide (the starting daily dose for liraglutide for weight loss, available as Saxenda, Novo Nordisk) given the evening before testing.
The findings, from 30 adults with normal insulin sensitivity and normal weight and 24 adults with impaired insulin sensitivity and obesity, suggest that metabolic signals, particularly ones that promote energy restoration in a setting of energy deprivation caused by insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, “profoundly influence neuronal processing,” said Dr. Tittgemeyer. The findings suggest that impaired metabolic signaling such as occurs with insulin resistance in people with obesity can cause deficiencies in associative learning.
‘Liraglutide can normalize learning of associations’
“We show that in people with obesity, disrupted circuit mechanisms lead to impaired learning about sensory associations,” Dr. Tittgemeyer said in an interview. “The information provided by sensory systems that the brain must interpret to select a behavioral response are ‘off tune’ ” in these individuals.
“This is rather consequential for understanding food-intake behaviors. Modern obesity treatments, such as liraglutide, can normalize learning of associations and thereby render people susceptible again for sensory signals and make them more prone to react to subliminal interactions, such as weight-normalizing diets and conscious eating,” he added.
The normalization in associative learning that one dose of liraglutide produced in people with obesity “fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” he explained.
Dr. Tittgemeyer noted that this effect is likely shared by other agents in the GLP-1 receptor agonist class, such as semaglutide (Ozempic, Wegovy, Novo Nordisk) but is likely not an effect when agents agonize receptors to other nutrient-stimulated hormones such as glucagon and the glucose-dependent insulinotropic polypeptide.
The findings “show that liraglutide restores associative learning in participants with greater insulin resistance,” a “highly relevant” discovery, commented Nils B. Kroemer, PhD, head of the section of medical psychology at the University of Bonn, Germany, who was not involved with this research, in a written statement.
The study run by Dr. Tittgemeyer and his associates included 54 healthy adult volunteers whom they assessed for insulin sensitivity with their homeostasis model assessment of insulin resistance. The researchers divided the cohort into groups; one group included 24 people with impaired insulin sensitivity, and one included 30 with normal insulin sensitivity. The average body mass index (BMI) of the normal sensitivity group was about 24 kg/m2; in the insulin-resistant subgroup, BMI averaged about 33 kg/m2.
The associative learning task tested the ability of participants to learn associations between auditory cues (a high or low tone) and a subsequent visual outcome (a picture of a face or a house). During each associative learning session, participants also underwent functional MRI of the brain.
Liraglutide treatment leveled learning
The results showed that the learning rate was significantly lower in the subgroup with impaired insulin sensitivity, compared with those with normal insulin sensitivity following treatment with a placebo injection. This indicates a decreased adaptation of learning to predictability variations in individuals with impaired insulin sensitivity.
In contrast, treatment with a single dose of liraglutide significantly enhanced the learning rate in the group with impaired insulin sensitivity but significantly reduced the learning rate in the group with normal insulin sensitivity. Liraglutide’s effect was twice as large in the group with impaired insulin sensitivity than in the group with normal insulin sensitivity, and these opposing effects of liraglutide resulted in a convergence of the two groups’ adaptive learning rates so that there wasn’t any significant between-group difference following liraglutide treatment.
After analyzing the functional MRI data along with the learning results, the researchers concluded that liraglutide normalized learning in individuals with impaired insulin sensitivity by enhancing adaptive prediction error encoding in the brain’s ventral striatum and mesocortical projection sites.
This apparent ability of GLP-1 analogues to correct this learning deficit in people with impaired insulin sensitivity and obesity has implications regarding potential benefit for people with other pathologies characterized by impaired dopaminergic function and associated with metabolic impairments, such as psychosis, Parkinson’s disease, and depression, the researchers say.
“The fascinating thing about GLP-1 receptor agonists is that they have an additional mechanism that relates to anti-inflammatory effects, especially for alleviating cell stress,” said Dr. Tittgemeyer. “Many ongoing clinical trials are assessing their effects in neuropsychiatric diseases,” he noted.
The study received no commercial funding. Dr. Tittgemyer and most of his coauthors had no disclosures. One coauthor had several disclosures, which are detailed in the report. Dr. Kroemer had no disclosures.
A version of this article first appeared on Medscape.com.
A single injection of the GLP-1 receptor agonist liraglutide led to short-term normalization of associative learning in people with obesity and insulin resistance, a finding that suggests say the authors of a recent report in Nature Metabolism.
“We demonstrated that dopamine-driven associative learning about external sensory cues crucially depends on metabolic signaling,” said Marc Tittgemeyer, PhD, professor at the Max Planck Institute for Metabolism Research in Cologne, Germany, and senior author of the study. Study participants with impaired insulin sensitivity “exhibited a reduced amplitude of behavioral updating that was normalized” by a single subcutaneous injection of 0.6 mg of liraglutide (the starting daily dose for liraglutide for weight loss, available as Saxenda, Novo Nordisk) given the evening before testing.
The findings, from 30 adults with normal insulin sensitivity and normal weight and 24 adults with impaired insulin sensitivity and obesity, suggest that metabolic signals, particularly ones that promote energy restoration in a setting of energy deprivation caused by insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, “profoundly influence neuronal processing,” said Dr. Tittgemeyer. The findings suggest that impaired metabolic signaling such as occurs with insulin resistance in people with obesity can cause deficiencies in associative learning.
‘Liraglutide can normalize learning of associations’
“We show that in people with obesity, disrupted circuit mechanisms lead to impaired learning about sensory associations,” Dr. Tittgemeyer said in an interview. “The information provided by sensory systems that the brain must interpret to select a behavioral response are ‘off tune’ ” in these individuals.
“This is rather consequential for understanding food-intake behaviors. Modern obesity treatments, such as liraglutide, can normalize learning of associations and thereby render people susceptible again for sensory signals and make them more prone to react to subliminal interactions, such as weight-normalizing diets and conscious eating,” he added.
The normalization in associative learning that one dose of liraglutide produced in people with obesity “fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” he explained.
Dr. Tittgemeyer noted that this effect is likely shared by other agents in the GLP-1 receptor agonist class, such as semaglutide (Ozempic, Wegovy, Novo Nordisk) but is likely not an effect when agents agonize receptors to other nutrient-stimulated hormones such as glucagon and the glucose-dependent insulinotropic polypeptide.
The findings “show that liraglutide restores associative learning in participants with greater insulin resistance,” a “highly relevant” discovery, commented Nils B. Kroemer, PhD, head of the section of medical psychology at the University of Bonn, Germany, who was not involved with this research, in a written statement.
The study run by Dr. Tittgemeyer and his associates included 54 healthy adult volunteers whom they assessed for insulin sensitivity with their homeostasis model assessment of insulin resistance. The researchers divided the cohort into groups; one group included 24 people with impaired insulin sensitivity, and one included 30 with normal insulin sensitivity. The average body mass index (BMI) of the normal sensitivity group was about 24 kg/m2; in the insulin-resistant subgroup, BMI averaged about 33 kg/m2.
The associative learning task tested the ability of participants to learn associations between auditory cues (a high or low tone) and a subsequent visual outcome (a picture of a face or a house). During each associative learning session, participants also underwent functional MRI of the brain.
Liraglutide treatment leveled learning
The results showed that the learning rate was significantly lower in the subgroup with impaired insulin sensitivity, compared with those with normal insulin sensitivity following treatment with a placebo injection. This indicates a decreased adaptation of learning to predictability variations in individuals with impaired insulin sensitivity.
In contrast, treatment with a single dose of liraglutide significantly enhanced the learning rate in the group with impaired insulin sensitivity but significantly reduced the learning rate in the group with normal insulin sensitivity. Liraglutide’s effect was twice as large in the group with impaired insulin sensitivity than in the group with normal insulin sensitivity, and these opposing effects of liraglutide resulted in a convergence of the two groups’ adaptive learning rates so that there wasn’t any significant between-group difference following liraglutide treatment.
After analyzing the functional MRI data along with the learning results, the researchers concluded that liraglutide normalized learning in individuals with impaired insulin sensitivity by enhancing adaptive prediction error encoding in the brain’s ventral striatum and mesocortical projection sites.
This apparent ability of GLP-1 analogues to correct this learning deficit in people with impaired insulin sensitivity and obesity has implications regarding potential benefit for people with other pathologies characterized by impaired dopaminergic function and associated with metabolic impairments, such as psychosis, Parkinson’s disease, and depression, the researchers say.
“The fascinating thing about GLP-1 receptor agonists is that they have an additional mechanism that relates to anti-inflammatory effects, especially for alleviating cell stress,” said Dr. Tittgemeyer. “Many ongoing clinical trials are assessing their effects in neuropsychiatric diseases,” he noted.
The study received no commercial funding. Dr. Tittgemyer and most of his coauthors had no disclosures. One coauthor had several disclosures, which are detailed in the report. Dr. Kroemer had no disclosures.
A version of this article first appeared on Medscape.com.
A single injection of the GLP-1 receptor agonist liraglutide led to short-term normalization of associative learning in people with obesity and insulin resistance, a finding that suggests say the authors of a recent report in Nature Metabolism.
“We demonstrated that dopamine-driven associative learning about external sensory cues crucially depends on metabolic signaling,” said Marc Tittgemeyer, PhD, professor at the Max Planck Institute for Metabolism Research in Cologne, Germany, and senior author of the study. Study participants with impaired insulin sensitivity “exhibited a reduced amplitude of behavioral updating that was normalized” by a single subcutaneous injection of 0.6 mg of liraglutide (the starting daily dose for liraglutide for weight loss, available as Saxenda, Novo Nordisk) given the evening before testing.
The findings, from 30 adults with normal insulin sensitivity and normal weight and 24 adults with impaired insulin sensitivity and obesity, suggest that metabolic signals, particularly ones that promote energy restoration in a setting of energy deprivation caused by insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist, “profoundly influence neuronal processing,” said Dr. Tittgemeyer. The findings suggest that impaired metabolic signaling such as occurs with insulin resistance in people with obesity can cause deficiencies in associative learning.
‘Liraglutide can normalize learning of associations’
“We show that in people with obesity, disrupted circuit mechanisms lead to impaired learning about sensory associations,” Dr. Tittgemeyer said in an interview. “The information provided by sensory systems that the brain must interpret to select a behavioral response are ‘off tune’ ” in these individuals.
“This is rather consequential for understanding food-intake behaviors. Modern obesity treatments, such as liraglutide, can normalize learning of associations and thereby render people susceptible again for sensory signals and make them more prone to react to subliminal interactions, such as weight-normalizing diets and conscious eating,” he added.
The normalization in associative learning that one dose of liraglutide produced in people with obesity “fits with studies showing that these drugs restore a normal feeling of satiety, causing people to eat less and therefore lose weight,” he explained.
Dr. Tittgemeyer noted that this effect is likely shared by other agents in the GLP-1 receptor agonist class, such as semaglutide (Ozempic, Wegovy, Novo Nordisk) but is likely not an effect when agents agonize receptors to other nutrient-stimulated hormones such as glucagon and the glucose-dependent insulinotropic polypeptide.
The findings “show that liraglutide restores associative learning in participants with greater insulin resistance,” a “highly relevant” discovery, commented Nils B. Kroemer, PhD, head of the section of medical psychology at the University of Bonn, Germany, who was not involved with this research, in a written statement.
The study run by Dr. Tittgemeyer and his associates included 54 healthy adult volunteers whom they assessed for insulin sensitivity with their homeostasis model assessment of insulin resistance. The researchers divided the cohort into groups; one group included 24 people with impaired insulin sensitivity, and one included 30 with normal insulin sensitivity. The average body mass index (BMI) of the normal sensitivity group was about 24 kg/m2; in the insulin-resistant subgroup, BMI averaged about 33 kg/m2.
The associative learning task tested the ability of participants to learn associations between auditory cues (a high or low tone) and a subsequent visual outcome (a picture of a face or a house). During each associative learning session, participants also underwent functional MRI of the brain.
Liraglutide treatment leveled learning
The results showed that the learning rate was significantly lower in the subgroup with impaired insulin sensitivity, compared with those with normal insulin sensitivity following treatment with a placebo injection. This indicates a decreased adaptation of learning to predictability variations in individuals with impaired insulin sensitivity.
In contrast, treatment with a single dose of liraglutide significantly enhanced the learning rate in the group with impaired insulin sensitivity but significantly reduced the learning rate in the group with normal insulin sensitivity. Liraglutide’s effect was twice as large in the group with impaired insulin sensitivity than in the group with normal insulin sensitivity, and these opposing effects of liraglutide resulted in a convergence of the two groups’ adaptive learning rates so that there wasn’t any significant between-group difference following liraglutide treatment.
After analyzing the functional MRI data along with the learning results, the researchers concluded that liraglutide normalized learning in individuals with impaired insulin sensitivity by enhancing adaptive prediction error encoding in the brain’s ventral striatum and mesocortical projection sites.
This apparent ability of GLP-1 analogues to correct this learning deficit in people with impaired insulin sensitivity and obesity has implications regarding potential benefit for people with other pathologies characterized by impaired dopaminergic function and associated with metabolic impairments, such as psychosis, Parkinson’s disease, and depression, the researchers say.
“The fascinating thing about GLP-1 receptor agonists is that they have an additional mechanism that relates to anti-inflammatory effects, especially for alleviating cell stress,” said Dr. Tittgemeyer. “Many ongoing clinical trials are assessing their effects in neuropsychiatric diseases,” he noted.
The study received no commercial funding. Dr. Tittgemyer and most of his coauthors had no disclosures. One coauthor had several disclosures, which are detailed in the report. Dr. Kroemer had no disclosures.
A version of this article first appeared on Medscape.com.
FROM NATURE METABOLISM
Apple cider vinegar, fenugreek best herbal remedies for T2D: Review
The review included 44 randomized clinical trials with more than 3,000 participants using six herbal remedies: apple cider vinegar, cinnamon, curcumin, fenugreek seeds, ginger, and saffron.
Apple cider vinegar, fenugreek seeds, curcumin (turmeric), and cinnamon resulted in statistically significant reductions in fasting blood glucose, compared with the control groups in the clinical trials. Out of all the remedies, the authors found apple cider vinegar to be the most effective for lowering fasting blood glucose levels.
The review also found that apple cider vinegar and fenugreek seeds had a statistically significant effect on reducing A1c, compared with the control groups. The authors found the herbal remedies made no difference to insulin level or homeostatic model assessment for insulin resistance (HOMA-IR).
The results are published online in Diabetes & Metabolic Syndrome: Clinical Research & Reviews. The authors said they hoped the review would help medical professionals and people with type 2 diabetes understand the effectiveness of different herbal remedies and consider incorporating these remedies into standard care.
“Some people use curcumin, some use ginger, some use apple cider [vinegar], but it’s not clear which is better,” said Shiv Mudgal, PhD, corresponding author of the paper and an associate professor in nursing at the All India Institute of Medical Sciences in Deoghar, India.
“We thought it would be nice to get some idea about how they work and how they compete with each other,” said Subodh Kumar, MD, the first author and an associate professor in pharmacology at the All India Institute of Medical Sciences in Deoghar, India.
They wanted to understand how the herbal remedies worked by including insulin level and HOMA-IR as measurable outcomes but found nothing conclusive. Instead, they speculated that the effect of apple cider vinegar and fenugreek seeds on blood glucose and A1c could be related to delayed gastric emptying, among other mechanisms.
However, the results should be interpreted with caution, said Dr. Kumar.
Apple cider vinegar had three clinical trials to back the finding, and fenugreek seeds had four studies supporting the results – fewer than the other included remedies. The authors also identified risks of bias from the randomization process and the allocation concealment process in several of the included trials.
Most of the studies included only short follow-up periods, meaning that the long-term effects of using these herbal remedies to help manage type 2 diabetes remain unclear.
The six herbal remedies included in the study were chosen out of dozens of popular complementary medicines for the strength and number of clinical trials backing their use.
The limited number included in the review is a drawback, according to Merlin Willcox, DPhil, a clinical lecturer in general practice at the University of Southampton, England, who was not involved in the research.
“It means they’ve left out stuff that’s potentially effective,” Dr. Willcox said in an interview.
Dr. Willcox, who has coauthored a review of herbal remedies for glycemic control in type 2 diabetes, said he was surprised that apple cider vinegar came out on top in this analysis.
His review concluded that aloe vera leaf gel, psyllium fiber, and fenugreek seeds appeared to be the most effective at reducing A1c, compared with the control groups of the included trials, out of 18 plant-based remedies.
There were no adverse effects associated with the herbal remedies, according to Dr. Mudgal. However, the evidence for the herbal remedies included in their review also lacked substantial follow-up periods assessing their long-term effects.
“You need to look at the evidence for each individual remedy; it’s not just about what plant it is, but it’s about what preparation, what dose. All of that comes into play,” Dr. Willcox said.
Up to 3.6 million people use herbal remedies to manage type 2 diabetes in the United States, according to a 2014 study cited by the review authors. The number is much higher elsewhere: As many as two-thirds of patients with diabetes in India and Saudi Arabia incorporate herbal remedies to help manage symptoms, whereas about half of patients with diabetes in the United Kingdom use herbal medicines.
Experts warn of the risks associated with using herbal medicines to complement traditional therapies.
“I caution my patients about dietary supplements and herbals because of the lack of high-quality data demonstrating efficacy and safety,” Katherine H. Saunders, MD, DABOM, cofounder of Intellihealth and clinical assistant professor of medicine at Weill Cornell Medicine, New York, said in an interview.
For Dr. Willcox, the risks relate to where patients get their information from. Many patients with type 2 diabetes are too scared to talk to their doctor about herbal medicines.
“They think their doctor is going to be negative or dismissive,” Dr. Willcox said. “So patients are getting their information from family and friends or from the Internet, which is not necessarily the most reliable, evidence-based source of information.”
The authors have reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
The review included 44 randomized clinical trials with more than 3,000 participants using six herbal remedies: apple cider vinegar, cinnamon, curcumin, fenugreek seeds, ginger, and saffron.
Apple cider vinegar, fenugreek seeds, curcumin (turmeric), and cinnamon resulted in statistically significant reductions in fasting blood glucose, compared with the control groups in the clinical trials. Out of all the remedies, the authors found apple cider vinegar to be the most effective for lowering fasting blood glucose levels.
The review also found that apple cider vinegar and fenugreek seeds had a statistically significant effect on reducing A1c, compared with the control groups. The authors found the herbal remedies made no difference to insulin level or homeostatic model assessment for insulin resistance (HOMA-IR).
The results are published online in Diabetes & Metabolic Syndrome: Clinical Research & Reviews. The authors said they hoped the review would help medical professionals and people with type 2 diabetes understand the effectiveness of different herbal remedies and consider incorporating these remedies into standard care.
“Some people use curcumin, some use ginger, some use apple cider [vinegar], but it’s not clear which is better,” said Shiv Mudgal, PhD, corresponding author of the paper and an associate professor in nursing at the All India Institute of Medical Sciences in Deoghar, India.
“We thought it would be nice to get some idea about how they work and how they compete with each other,” said Subodh Kumar, MD, the first author and an associate professor in pharmacology at the All India Institute of Medical Sciences in Deoghar, India.
They wanted to understand how the herbal remedies worked by including insulin level and HOMA-IR as measurable outcomes but found nothing conclusive. Instead, they speculated that the effect of apple cider vinegar and fenugreek seeds on blood glucose and A1c could be related to delayed gastric emptying, among other mechanisms.
However, the results should be interpreted with caution, said Dr. Kumar.
Apple cider vinegar had three clinical trials to back the finding, and fenugreek seeds had four studies supporting the results – fewer than the other included remedies. The authors also identified risks of bias from the randomization process and the allocation concealment process in several of the included trials.
Most of the studies included only short follow-up periods, meaning that the long-term effects of using these herbal remedies to help manage type 2 diabetes remain unclear.
The six herbal remedies included in the study were chosen out of dozens of popular complementary medicines for the strength and number of clinical trials backing their use.
The limited number included in the review is a drawback, according to Merlin Willcox, DPhil, a clinical lecturer in general practice at the University of Southampton, England, who was not involved in the research.
“It means they’ve left out stuff that’s potentially effective,” Dr. Willcox said in an interview.
Dr. Willcox, who has coauthored a review of herbal remedies for glycemic control in type 2 diabetes, said he was surprised that apple cider vinegar came out on top in this analysis.
His review concluded that aloe vera leaf gel, psyllium fiber, and fenugreek seeds appeared to be the most effective at reducing A1c, compared with the control groups of the included trials, out of 18 plant-based remedies.
There were no adverse effects associated with the herbal remedies, according to Dr. Mudgal. However, the evidence for the herbal remedies included in their review also lacked substantial follow-up periods assessing their long-term effects.
“You need to look at the evidence for each individual remedy; it’s not just about what plant it is, but it’s about what preparation, what dose. All of that comes into play,” Dr. Willcox said.
Up to 3.6 million people use herbal remedies to manage type 2 diabetes in the United States, according to a 2014 study cited by the review authors. The number is much higher elsewhere: As many as two-thirds of patients with diabetes in India and Saudi Arabia incorporate herbal remedies to help manage symptoms, whereas about half of patients with diabetes in the United Kingdom use herbal medicines.
Experts warn of the risks associated with using herbal medicines to complement traditional therapies.
“I caution my patients about dietary supplements and herbals because of the lack of high-quality data demonstrating efficacy and safety,” Katherine H. Saunders, MD, DABOM, cofounder of Intellihealth and clinical assistant professor of medicine at Weill Cornell Medicine, New York, said in an interview.
For Dr. Willcox, the risks relate to where patients get their information from. Many patients with type 2 diabetes are too scared to talk to their doctor about herbal medicines.
“They think their doctor is going to be negative or dismissive,” Dr. Willcox said. “So patients are getting their information from family and friends or from the Internet, which is not necessarily the most reliable, evidence-based source of information.”
The authors have reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
The review included 44 randomized clinical trials with more than 3,000 participants using six herbal remedies: apple cider vinegar, cinnamon, curcumin, fenugreek seeds, ginger, and saffron.
Apple cider vinegar, fenugreek seeds, curcumin (turmeric), and cinnamon resulted in statistically significant reductions in fasting blood glucose, compared with the control groups in the clinical trials. Out of all the remedies, the authors found apple cider vinegar to be the most effective for lowering fasting blood glucose levels.
The review also found that apple cider vinegar and fenugreek seeds had a statistically significant effect on reducing A1c, compared with the control groups. The authors found the herbal remedies made no difference to insulin level or homeostatic model assessment for insulin resistance (HOMA-IR).
The results are published online in Diabetes & Metabolic Syndrome: Clinical Research & Reviews. The authors said they hoped the review would help medical professionals and people with type 2 diabetes understand the effectiveness of different herbal remedies and consider incorporating these remedies into standard care.
“Some people use curcumin, some use ginger, some use apple cider [vinegar], but it’s not clear which is better,” said Shiv Mudgal, PhD, corresponding author of the paper and an associate professor in nursing at the All India Institute of Medical Sciences in Deoghar, India.
“We thought it would be nice to get some idea about how they work and how they compete with each other,” said Subodh Kumar, MD, the first author and an associate professor in pharmacology at the All India Institute of Medical Sciences in Deoghar, India.
They wanted to understand how the herbal remedies worked by including insulin level and HOMA-IR as measurable outcomes but found nothing conclusive. Instead, they speculated that the effect of apple cider vinegar and fenugreek seeds on blood glucose and A1c could be related to delayed gastric emptying, among other mechanisms.
However, the results should be interpreted with caution, said Dr. Kumar.
Apple cider vinegar had three clinical trials to back the finding, and fenugreek seeds had four studies supporting the results – fewer than the other included remedies. The authors also identified risks of bias from the randomization process and the allocation concealment process in several of the included trials.
Most of the studies included only short follow-up periods, meaning that the long-term effects of using these herbal remedies to help manage type 2 diabetes remain unclear.
The six herbal remedies included in the study were chosen out of dozens of popular complementary medicines for the strength and number of clinical trials backing their use.
The limited number included in the review is a drawback, according to Merlin Willcox, DPhil, a clinical lecturer in general practice at the University of Southampton, England, who was not involved in the research.
“It means they’ve left out stuff that’s potentially effective,” Dr. Willcox said in an interview.
Dr. Willcox, who has coauthored a review of herbal remedies for glycemic control in type 2 diabetes, said he was surprised that apple cider vinegar came out on top in this analysis.
His review concluded that aloe vera leaf gel, psyllium fiber, and fenugreek seeds appeared to be the most effective at reducing A1c, compared with the control groups of the included trials, out of 18 plant-based remedies.
There were no adverse effects associated with the herbal remedies, according to Dr. Mudgal. However, the evidence for the herbal remedies included in their review also lacked substantial follow-up periods assessing their long-term effects.
“You need to look at the evidence for each individual remedy; it’s not just about what plant it is, but it’s about what preparation, what dose. All of that comes into play,” Dr. Willcox said.
Up to 3.6 million people use herbal remedies to manage type 2 diabetes in the United States, according to a 2014 study cited by the review authors. The number is much higher elsewhere: As many as two-thirds of patients with diabetes in India and Saudi Arabia incorporate herbal remedies to help manage symptoms, whereas about half of patients with diabetes in the United Kingdom use herbal medicines.
Experts warn of the risks associated with using herbal medicines to complement traditional therapies.
“I caution my patients about dietary supplements and herbals because of the lack of high-quality data demonstrating efficacy and safety,” Katherine H. Saunders, MD, DABOM, cofounder of Intellihealth and clinical assistant professor of medicine at Weill Cornell Medicine, New York, said in an interview.
For Dr. Willcox, the risks relate to where patients get their information from. Many patients with type 2 diabetes are too scared to talk to their doctor about herbal medicines.
“They think their doctor is going to be negative or dismissive,” Dr. Willcox said. “So patients are getting their information from family and friends or from the Internet, which is not necessarily the most reliable, evidence-based source of information.”
The authors have reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM DIABETES & METABOLIC SYNDROME: CLINICAL RESEARCH & REVIEWS
Artificial sweeteners no help for weight loss: Review
It also shows evidence that these products are not beneficial for controlling excess weight.
Francisco Gómez-Delgado, MD, PhD, and Pablo Pérez-Martínez, MD, PhD, are members of the Spanish Society of Arteriosclerosis and of the Spanish Society of Internal Medicine. They have coordinated an updated review of the leading scientific evidence surrounding artificial sweeteners: evidence showing that far from positively affecting our health, they have “negative effects for the cardiometabolic system.”
The paper, published in Current Opinion in Cardiology, delves into the consumption of these sweeteners and their negative influence on the development of obesity and of several of the most important cardiometabolic risk factors (hypertension, dyslipidemia, and diabetes).
Globalization and the increase in consumption of ultraprocessed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners (nutritive and nonnutritive). This review aims to analyze their role and their effect on cardiometabolic and cardiovascular disease risk.
Cardiovascular risk
The detrimental effects of a high-calorie, high-sugar diet have been well established. For this reason, health authorities recommend limiting sugar consumption. The recommendation has led the food industry to develop different artificial sweeteners with specific properties, such as flavor and stability (nutritive artificial sweeteners), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners). Recent evidence explores the influence of these two types of artificial sweeteners on cardiovascular disease risk through risk factors such as obesity and type 2 diabetes, among others.
Initially, the consumption of artificial sweeteners was presented as an alternative for reducing calorie intake in the diet as an option for people with excess weight and obesity. However, as this paper explains, the consumption of these artificial sweeteners favors weight gain because of neuroendocrine mechanisms related to satiety that are abnormally activated when artificial sweeteners are consumed.
Weight gain
On the other hand, evidence shows that consuming artificial sweeteners does not encourage weight loss. “Quite the contrary,” Dr. Pérez-Martínez, scientific director at the Maimonides Biomedical Research Institute and internist at the University Hospital Reina Sofia, both in Córdoba, told this news organization. “There is evidence showing weight gain resulting from the effect that artificial sweetener consumption has at the neurohormonal level by altering the mechanisms involved in regulating the feeling of satiety.”
However, on the basis of current evidence, sugar cannot be claimed to be less harmful. “What we do know is that in both cases, we should reduce or remove them from our diets and replace them with other healthier alternatives for weight management, such as eating plant-based products or being physically active.”
Confronting ignorance
Nonetheless, these recommendations are conditional, “because the weight of the evidence is not extremely high, since there have not been a whole lot of studies. All nutritional studies must be viewed with caution,” Manuel Anguita, MD, PhD, said in an interview. Dr. Anguita is department head of clinical cardiology at the University Hospital Reina Sofia in Córdoba and past president of the Spanish Society of Cardiology.
“It’s something that should be included within the medical record when you’re assessing cardiovascular risk. In addition to identifying patients who use artificial sweeteners, it’s especially important to emphasize that it’s not an appropriate recommendation for weight management.” Healthier measures include moderate exercise and the Mediterranean diet.
Explaining why this research is valuable, he said, “It’s generally useful because there’s ignorance not only in the population but among physicians as well [about] these negative effects of sweeteners.”
Diabetes and metabolic syndrome
Artificial sweeteners cause significant disruptions in the endocrine system, leading our metabolism to function abnormally. The review revealed that consuming artificial sweeteners raises the risk for type 2 diabetes by between 18% and 24% and raises the risk for metabolic syndrome by up to 44%.
Dr. Gómez-Delgado, an internal medicine specialist at the University Hospital of Jaen in Spain and first author of the study, discussed the deleterious effects of sweeteners on metabolism. “On one hand, neurohormonal disorders impact appetite, and the feeling of satiety is abnormally delayed.” On the other hand, “they induce excessive insulin secretion in the pancreas,” which in the long run, encourages metabolic disorders that lead to diabetes. Ultimately, this process produces what we know as “dysbiosis, since our microbiota is unable to process these artificial sweeteners.” Dysbiosis triggers specific pathophysiologic processes that negatively affect cardiometabolic and cardiovascular systems.
No differences
Regarding the type of sweetener, Dr. Gómez-Delgado noted that currently available studies assess the consumption of special dietary products that, in most cases, include various types of artificial sweeteners. “So, it’s not possible to define specific differences between them as to how they impact our health.” Additional studies are needed to confirm this effect at the cardiometabolic level and to analyze the different types of artificial sweeteners individually.
“There’s enough evidence to confirm that consuming artificial sweeteners negatively interferes with our metabolism – especially glucose metabolism – and increases the risk of developing diabetes,” said Dr. Gómez-Delgado.
High-sodium drinks
When it comes to the influence of artificial sweeteners on hypertension, “there is no single explanation. The World Health Organization already discussed this issue 4-5 years ago, not only due to their carcinogenic risk, but also due to this cardiovascular risk in terms of a lack of control of obesity, diabetes, and hypertension,” said Dr. Anguita.
Another important point “is that this is not in reference to the sweeteners themselves, but to soft drinks containing those components, which is where we have more studies,” he added. There are two factors explaining this increase in hypertension, which poses a problem at the population level, with medium- to long-term follow-up. “The sugary beverages that we mentioned have a higher sodium content. That is, the sweeteners add this element, which is a factor that’s directly linked to the increase in blood pressure levels.” Another factor that can influence blood pressure is “the increase in insulin secretion that has been described as resulting from sweeteners. In the medium and long term, this is associated with increased blood pressure levels.”
Cardiovascular risk factor?
Are artificial sweeteners considered to be a new cardiovascular risk factor? “What they really do is increase the incidence of the other classic risk factors,” including obesity, said Dr. Anguita. It has been shown that artificial sweeteners don’t reduce obesity when used continuously. Nonetheless, “there is still not enough evidence to view it in the same light as the classic risk factors,” added Dr. Anguita. However, it is a factor that can clearly worsen the control of the other factors. Therefore, “it’s appropriate to sound an alarm and explain that it’s not the best way to lose weight; there are many other healthier choices.”
“We need more robust evidence to take a clear position on the use of this type of sweetener and its detrimental effect on health. Meanwhile, it would be ideal to limit their consumption or even avoid adding artificial sweeteners to coffee or teas,” added Dr. Pérez-Martínez.
Regulate consumption
Dr. Pérez-Martínez mentioned that the measures proposed to regulate the consumption of artificial sweeteners and to modify the current legislation must involve “minimizing the consumption of these special dietary products as much as possible and even avoiding adding these artificial sweeteners to the foods that we consume; for example, to coffee and tea.” On the other hand, “we must provide consumers with information that is as clear and simple as possible regarding the composition of the food they consume and how it impacts their health.”
However, “we need more evidence to be able to take a clear position on what type of sweeteners we can consume in our diet and also to what extent we should limit their presence in the foods we consume,” said Dr. Pérez-Martínez.
Last, “most of the evidence is from short-term observational studies that assess frequencies and patterns of consumption of foods containing these artificial sweeteners.” Of course, “we need studies that specifically analyze their effects at the metabolic level as well as longer-term studies where the nutritional follow-up of participants is more accurate and rigorous, especially when it comes to the consumption of this type of food,” concluded Dr. Gómez-Delgado.
This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.
It also shows evidence that these products are not beneficial for controlling excess weight.
Francisco Gómez-Delgado, MD, PhD, and Pablo Pérez-Martínez, MD, PhD, are members of the Spanish Society of Arteriosclerosis and of the Spanish Society of Internal Medicine. They have coordinated an updated review of the leading scientific evidence surrounding artificial sweeteners: evidence showing that far from positively affecting our health, they have “negative effects for the cardiometabolic system.”
The paper, published in Current Opinion in Cardiology, delves into the consumption of these sweeteners and their negative influence on the development of obesity and of several of the most important cardiometabolic risk factors (hypertension, dyslipidemia, and diabetes).
Globalization and the increase in consumption of ultraprocessed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners (nutritive and nonnutritive). This review aims to analyze their role and their effect on cardiometabolic and cardiovascular disease risk.
Cardiovascular risk
The detrimental effects of a high-calorie, high-sugar diet have been well established. For this reason, health authorities recommend limiting sugar consumption. The recommendation has led the food industry to develop different artificial sweeteners with specific properties, such as flavor and stability (nutritive artificial sweeteners), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners). Recent evidence explores the influence of these two types of artificial sweeteners on cardiovascular disease risk through risk factors such as obesity and type 2 diabetes, among others.
Initially, the consumption of artificial sweeteners was presented as an alternative for reducing calorie intake in the diet as an option for people with excess weight and obesity. However, as this paper explains, the consumption of these artificial sweeteners favors weight gain because of neuroendocrine mechanisms related to satiety that are abnormally activated when artificial sweeteners are consumed.
Weight gain
On the other hand, evidence shows that consuming artificial sweeteners does not encourage weight loss. “Quite the contrary,” Dr. Pérez-Martínez, scientific director at the Maimonides Biomedical Research Institute and internist at the University Hospital Reina Sofia, both in Córdoba, told this news organization. “There is evidence showing weight gain resulting from the effect that artificial sweetener consumption has at the neurohormonal level by altering the mechanisms involved in regulating the feeling of satiety.”
However, on the basis of current evidence, sugar cannot be claimed to be less harmful. “What we do know is that in both cases, we should reduce or remove them from our diets and replace them with other healthier alternatives for weight management, such as eating plant-based products or being physically active.”
Confronting ignorance
Nonetheless, these recommendations are conditional, “because the weight of the evidence is not extremely high, since there have not been a whole lot of studies. All nutritional studies must be viewed with caution,” Manuel Anguita, MD, PhD, said in an interview. Dr. Anguita is department head of clinical cardiology at the University Hospital Reina Sofia in Córdoba and past president of the Spanish Society of Cardiology.
“It’s something that should be included within the medical record when you’re assessing cardiovascular risk. In addition to identifying patients who use artificial sweeteners, it’s especially important to emphasize that it’s not an appropriate recommendation for weight management.” Healthier measures include moderate exercise and the Mediterranean diet.
Explaining why this research is valuable, he said, “It’s generally useful because there’s ignorance not only in the population but among physicians as well [about] these negative effects of sweeteners.”
Diabetes and metabolic syndrome
Artificial sweeteners cause significant disruptions in the endocrine system, leading our metabolism to function abnormally. The review revealed that consuming artificial sweeteners raises the risk for type 2 diabetes by between 18% and 24% and raises the risk for metabolic syndrome by up to 44%.
Dr. Gómez-Delgado, an internal medicine specialist at the University Hospital of Jaen in Spain and first author of the study, discussed the deleterious effects of sweeteners on metabolism. “On one hand, neurohormonal disorders impact appetite, and the feeling of satiety is abnormally delayed.” On the other hand, “they induce excessive insulin secretion in the pancreas,” which in the long run, encourages metabolic disorders that lead to diabetes. Ultimately, this process produces what we know as “dysbiosis, since our microbiota is unable to process these artificial sweeteners.” Dysbiosis triggers specific pathophysiologic processes that negatively affect cardiometabolic and cardiovascular systems.
No differences
Regarding the type of sweetener, Dr. Gómez-Delgado noted that currently available studies assess the consumption of special dietary products that, in most cases, include various types of artificial sweeteners. “So, it’s not possible to define specific differences between them as to how they impact our health.” Additional studies are needed to confirm this effect at the cardiometabolic level and to analyze the different types of artificial sweeteners individually.
“There’s enough evidence to confirm that consuming artificial sweeteners negatively interferes with our metabolism – especially glucose metabolism – and increases the risk of developing diabetes,” said Dr. Gómez-Delgado.
High-sodium drinks
When it comes to the influence of artificial sweeteners on hypertension, “there is no single explanation. The World Health Organization already discussed this issue 4-5 years ago, not only due to their carcinogenic risk, but also due to this cardiovascular risk in terms of a lack of control of obesity, diabetes, and hypertension,” said Dr. Anguita.
Another important point “is that this is not in reference to the sweeteners themselves, but to soft drinks containing those components, which is where we have more studies,” he added. There are two factors explaining this increase in hypertension, which poses a problem at the population level, with medium- to long-term follow-up. “The sugary beverages that we mentioned have a higher sodium content. That is, the sweeteners add this element, which is a factor that’s directly linked to the increase in blood pressure levels.” Another factor that can influence blood pressure is “the increase in insulin secretion that has been described as resulting from sweeteners. In the medium and long term, this is associated with increased blood pressure levels.”
Cardiovascular risk factor?
Are artificial sweeteners considered to be a new cardiovascular risk factor? “What they really do is increase the incidence of the other classic risk factors,” including obesity, said Dr. Anguita. It has been shown that artificial sweeteners don’t reduce obesity when used continuously. Nonetheless, “there is still not enough evidence to view it in the same light as the classic risk factors,” added Dr. Anguita. However, it is a factor that can clearly worsen the control of the other factors. Therefore, “it’s appropriate to sound an alarm and explain that it’s not the best way to lose weight; there are many other healthier choices.”
“We need more robust evidence to take a clear position on the use of this type of sweetener and its detrimental effect on health. Meanwhile, it would be ideal to limit their consumption or even avoid adding artificial sweeteners to coffee or teas,” added Dr. Pérez-Martínez.
Regulate consumption
Dr. Pérez-Martínez mentioned that the measures proposed to regulate the consumption of artificial sweeteners and to modify the current legislation must involve “minimizing the consumption of these special dietary products as much as possible and even avoiding adding these artificial sweeteners to the foods that we consume; for example, to coffee and tea.” On the other hand, “we must provide consumers with information that is as clear and simple as possible regarding the composition of the food they consume and how it impacts their health.”
However, “we need more evidence to be able to take a clear position on what type of sweeteners we can consume in our diet and also to what extent we should limit their presence in the foods we consume,” said Dr. Pérez-Martínez.
Last, “most of the evidence is from short-term observational studies that assess frequencies and patterns of consumption of foods containing these artificial sweeteners.” Of course, “we need studies that specifically analyze their effects at the metabolic level as well as longer-term studies where the nutritional follow-up of participants is more accurate and rigorous, especially when it comes to the consumption of this type of food,” concluded Dr. Gómez-Delgado.
This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.
It also shows evidence that these products are not beneficial for controlling excess weight.
Francisco Gómez-Delgado, MD, PhD, and Pablo Pérez-Martínez, MD, PhD, are members of the Spanish Society of Arteriosclerosis and of the Spanish Society of Internal Medicine. They have coordinated an updated review of the leading scientific evidence surrounding artificial sweeteners: evidence showing that far from positively affecting our health, they have “negative effects for the cardiometabolic system.”
The paper, published in Current Opinion in Cardiology, delves into the consumption of these sweeteners and their negative influence on the development of obesity and of several of the most important cardiometabolic risk factors (hypertension, dyslipidemia, and diabetes).
Globalization and the increase in consumption of ultraprocessed foods have led to a need for greater knowledge on the health impacts of certain nutrients such as artificial sweeteners (nutritive and nonnutritive). This review aims to analyze their role and their effect on cardiometabolic and cardiovascular disease risk.
Cardiovascular risk
The detrimental effects of a high-calorie, high-sugar diet have been well established. For this reason, health authorities recommend limiting sugar consumption. The recommendation has led the food industry to develop different artificial sweeteners with specific properties, such as flavor and stability (nutritive artificial sweeteners), and others aimed at limiting sugar in the diet (nonnutritive artificial sweeteners). Recent evidence explores the influence of these two types of artificial sweeteners on cardiovascular disease risk through risk factors such as obesity and type 2 diabetes, among others.
Initially, the consumption of artificial sweeteners was presented as an alternative for reducing calorie intake in the diet as an option for people with excess weight and obesity. However, as this paper explains, the consumption of these artificial sweeteners favors weight gain because of neuroendocrine mechanisms related to satiety that are abnormally activated when artificial sweeteners are consumed.
Weight gain
On the other hand, evidence shows that consuming artificial sweeteners does not encourage weight loss. “Quite the contrary,” Dr. Pérez-Martínez, scientific director at the Maimonides Biomedical Research Institute and internist at the University Hospital Reina Sofia, both in Córdoba, told this news organization. “There is evidence showing weight gain resulting from the effect that artificial sweetener consumption has at the neurohormonal level by altering the mechanisms involved in regulating the feeling of satiety.”
However, on the basis of current evidence, sugar cannot be claimed to be less harmful. “What we do know is that in both cases, we should reduce or remove them from our diets and replace them with other healthier alternatives for weight management, such as eating plant-based products or being physically active.”
Confronting ignorance
Nonetheless, these recommendations are conditional, “because the weight of the evidence is not extremely high, since there have not been a whole lot of studies. All nutritional studies must be viewed with caution,” Manuel Anguita, MD, PhD, said in an interview. Dr. Anguita is department head of clinical cardiology at the University Hospital Reina Sofia in Córdoba and past president of the Spanish Society of Cardiology.
“It’s something that should be included within the medical record when you’re assessing cardiovascular risk. In addition to identifying patients who use artificial sweeteners, it’s especially important to emphasize that it’s not an appropriate recommendation for weight management.” Healthier measures include moderate exercise and the Mediterranean diet.
Explaining why this research is valuable, he said, “It’s generally useful because there’s ignorance not only in the population but among physicians as well [about] these negative effects of sweeteners.”
Diabetes and metabolic syndrome
Artificial sweeteners cause significant disruptions in the endocrine system, leading our metabolism to function abnormally. The review revealed that consuming artificial sweeteners raises the risk for type 2 diabetes by between 18% and 24% and raises the risk for metabolic syndrome by up to 44%.
Dr. Gómez-Delgado, an internal medicine specialist at the University Hospital of Jaen in Spain and first author of the study, discussed the deleterious effects of sweeteners on metabolism. “On one hand, neurohormonal disorders impact appetite, and the feeling of satiety is abnormally delayed.” On the other hand, “they induce excessive insulin secretion in the pancreas,” which in the long run, encourages metabolic disorders that lead to diabetes. Ultimately, this process produces what we know as “dysbiosis, since our microbiota is unable to process these artificial sweeteners.” Dysbiosis triggers specific pathophysiologic processes that negatively affect cardiometabolic and cardiovascular systems.
No differences
Regarding the type of sweetener, Dr. Gómez-Delgado noted that currently available studies assess the consumption of special dietary products that, in most cases, include various types of artificial sweeteners. “So, it’s not possible to define specific differences between them as to how they impact our health.” Additional studies are needed to confirm this effect at the cardiometabolic level and to analyze the different types of artificial sweeteners individually.
“There’s enough evidence to confirm that consuming artificial sweeteners negatively interferes with our metabolism – especially glucose metabolism – and increases the risk of developing diabetes,” said Dr. Gómez-Delgado.
High-sodium drinks
When it comes to the influence of artificial sweeteners on hypertension, “there is no single explanation. The World Health Organization already discussed this issue 4-5 years ago, not only due to their carcinogenic risk, but also due to this cardiovascular risk in terms of a lack of control of obesity, diabetes, and hypertension,” said Dr. Anguita.
Another important point “is that this is not in reference to the sweeteners themselves, but to soft drinks containing those components, which is where we have more studies,” he added. There are two factors explaining this increase in hypertension, which poses a problem at the population level, with medium- to long-term follow-up. “The sugary beverages that we mentioned have a higher sodium content. That is, the sweeteners add this element, which is a factor that’s directly linked to the increase in blood pressure levels.” Another factor that can influence blood pressure is “the increase in insulin secretion that has been described as resulting from sweeteners. In the medium and long term, this is associated with increased blood pressure levels.”
Cardiovascular risk factor?
Are artificial sweeteners considered to be a new cardiovascular risk factor? “What they really do is increase the incidence of the other classic risk factors,” including obesity, said Dr. Anguita. It has been shown that artificial sweeteners don’t reduce obesity when used continuously. Nonetheless, “there is still not enough evidence to view it in the same light as the classic risk factors,” added Dr. Anguita. However, it is a factor that can clearly worsen the control of the other factors. Therefore, “it’s appropriate to sound an alarm and explain that it’s not the best way to lose weight; there are many other healthier choices.”
“We need more robust evidence to take a clear position on the use of this type of sweetener and its detrimental effect on health. Meanwhile, it would be ideal to limit their consumption or even avoid adding artificial sweeteners to coffee or teas,” added Dr. Pérez-Martínez.
Regulate consumption
Dr. Pérez-Martínez mentioned that the measures proposed to regulate the consumption of artificial sweeteners and to modify the current legislation must involve “minimizing the consumption of these special dietary products as much as possible and even avoiding adding these artificial sweeteners to the foods that we consume; for example, to coffee and tea.” On the other hand, “we must provide consumers with information that is as clear and simple as possible regarding the composition of the food they consume and how it impacts their health.”
However, “we need more evidence to be able to take a clear position on what type of sweeteners we can consume in our diet and also to what extent we should limit their presence in the foods we consume,” said Dr. Pérez-Martínez.
Last, “most of the evidence is from short-term observational studies that assess frequencies and patterns of consumption of foods containing these artificial sweeteners.” Of course, “we need studies that specifically analyze their effects at the metabolic level as well as longer-term studies where the nutritional follow-up of participants is more accurate and rigorous, especially when it comes to the consumption of this type of food,” concluded Dr. Gómez-Delgado.
This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.
FROM CURRENT OPINION IN CARDIOLOGY