Neurology

Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed risk for dementia increased 3% for every 1 mg/m³ rise in fine particulate matter (PM_2.5) exposure.

Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.

While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.

“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.

The findings were published online in Neurology.
 

Conflicting results in past studies

Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.

Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM_2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.

After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m³ rise in PM_2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.

The study did not examine how or if the duration of PM_2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.

The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m³ to be safe. The World Health Organization sets that limit lower, at 5 mcg/m³.

Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.

“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”

Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.

Research also suggests that improving air quality PM_2.5 by just 10% results in a 14% decreased risk for dementia.
 

‘Impressive’ pattern

Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.

He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.

The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.

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

Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed risk for dementia increased 3% for every 1 mg/m³ rise in fine particulate matter (PM_2.5) exposure.

Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.

While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.

“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.

The findings were published online in Neurology.
 

Conflicting results in past studies

Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.

Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM_2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.

After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m³ rise in PM_2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.

The study did not examine how or if the duration of PM_2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.

The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m³ to be safe. The World Health Organization sets that limit lower, at 5 mcg/m³.

Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.

“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”

Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.

Research also suggests that improving air quality PM_2.5 by just 10% results in a 14% decreased risk for dementia.
 

‘Impressive’ pattern

Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.

He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.

The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.

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

Exposure to a traffic-related air pollutant significantly increases risk for dementia, new research suggests. Results from a meta-analysis, which included a total of more than 90 million people, showed risk for dementia increased 3% for every 1 mg/m³ rise in fine particulate matter (PM_2.5) exposure.

Particulate matter is a mixture of solid particles and liquid droplets from the burning of fossil fuels and nitrogen oxide, and also produced from road traffic exhaust.

While the research only showed an association between this type of air pollution and dementia risk, the estimates were consistent across the different analyses used.

“It’s rather sobering that there is this 3% relationship between incidence of dementia and the particulate matter and that it is such a precise estimate,” senior investigator Janet Martin, PharmD, MSc, associate professor of anesthesia & perioperative medicine and epidemiology & biostatistics at Western University’s, London, Ont., told this news organization.

The findings were published online in Neurology.
 

Conflicting results in past studies

Air pollution is a known risk factor for dementia, but studies attempting to pinpoint its exact impact have yielded conflicting results.

Researchers analyzed data from 17 studies with a total of 91.4 million individuals, 6% of whom had dementia. In addition to PM_2.5, the investigators also assessed nitrogen oxides, which form smog, nitrogen dioxide, and ozone exposure.

After adjustments for other known risk factors, such as age and gender, results showed that dementia risk increased by 3% for every 1 m³ rise in PM_2.5 exposure (adjusted hazard ratio, 1.03; 95% confidence interval, 1.02-1.05).

The associations between dementia and exposure to nitrogen oxides (HR, 1.05; 95% CI, 0.99-1.13), nitrogen dioxide (HR, 1.03; 95% CI, 1.00-1.07) and ozone (HR, 1.01; 95% CI, 0.91-1.11) did not reach statistical significance. However, the confidence intervals were wide enough that clinical relevance cannot be ruled out, Dr. Martin said.

The study did not examine how or if the duration of PM_2.5 exposure affected dementia risk. In addition, the investigators were not able to identify a threshold above which dementia risk begins to rise.

The Environmental Pollution Agency considers average yearly exposures up to 12 mcg/m³ to be safe. The World Health Organization sets that limit lower, at 5 mcg/m³.

Dr. Martin noted that more studies are needed to explore those issues, as well as the mechanisms by which air pollutants contribute to the pathology of dementia. However, the clear link between fine particulate matter exposure and increased risk emphasizes the need to address air pollution as a modifiable risk factor for dementia.

“The rising tide of dementia is not something we can easily reverse,” Dr. Martin said. “The evidence has been so elusive for how to treat dementia once you have it, so our biggest opportunity is to prevent it.”

Results from a study published earlier in 2022 estimated that rates of dementia will triple worldwide and double in the United States by 2050 unless steps are taking to mitigate risk factors.

Research also suggests that improving air quality PM_2.5 by just 10% results in a 14% decreased risk for dementia.
 

‘Impressive’ pattern

Paul Rosenberg, MD, codirector of the Memory and Alzheimer’s Treatment Center division of geriatric psychiatry at Johns Hopkins University, Baltimore, said that air pollution “is the most prominent environmental risk we’ve found” for dementia. It also “adds to many other lifestyle and comorbidity risks, such as lack of exercise, obesity, depression, hearing loss, etc,” said Dr. Rosenberg, who was not involved with the research.

He noted what was “most impressive” was that in most of the pooled studies, small particulate air pollution was associated with dementia. “The overall pattern is most impressive and the effect sizes quite consistent over most of the studies,” Dr. Rosenberg said.

The meta-analysis was unfunded. Dr. Martin and Dr. Rosenberg reported no relevant financial relationships.

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

The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.

The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.

Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”

In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.

In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.

Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.

“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”

He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”

In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
 

Prior research

Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.

Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.

Other past studies include:

• A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
• A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
• A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
• In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).

These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.

Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.

The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.

The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.

Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”

In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.

In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.

Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.

“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”

He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”

In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
 

Prior research

Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.

Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.

Other past studies include:

• A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
• A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
• A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
• In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).

These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.

Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.

The incidence of dementia in patients with rheumatoid arthritis who took either a biologic disease-modifying antirheumatic drug (bDMARD) or targeted synthetic DMARD (tsDMARD) was significantly lower than the rate observed in patients who take only a conventional synthetic DMARD (csDMARD) in a national database study.

The work builds on previous research indicating a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardinal symptoms of RA, its systemic inflammation leads to multiple systemic manifestations, offering biologically plausible links with cognitive decline. In addition, patients with RA have high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.

Chronic neuroinflammation secondary to either intrinsic or systemic stimuli is thought to play a key role in dementia development, especially Alzheimer’s dementia (AD). Research showing a role of tumor necrosis factor–alpha (TNF-alpha) in the development of dementia has piqued interest in a potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role in different stages of the pathophysiology and disease progression of Alzheimer’s disease,” study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vasculitis Center, said in an interview. “Animal models have shown that TNF inhibition reduces microgliosis, neuronal loss, and tau phosphorylation. Cognitive improvement has been seen in two trials with Alzheimer’s disease patients, but were not in rheumatoid arthritis patients.”

In the newest study, published online in Seminars in Arthritis and Rheumatism, Dr. Sattui and colleagues suggest that a lower risk for dementia seen with bDMARDs and tsDMARDs may be attributable to an overall greater decrease in inflammation rather than any mechanism of action specific to these drugs.

In the study of Centers for Medicare & Medicaid Services claims during 2006-2017 for 141,326 adult patients with RA, the crude incident rates were 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) for patients on csDMARDs and 1.3 (95% CI, 1.2-1.4) for patients on any b/tsDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of any DMARD. The adjusted risk for dementia among users of bDMARDs or tsDMARDs was 19% lower than the adjusted risk for patients on csDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between classes of bDMARDs or tsDMARDs.

Dr. Sattui and coauthors’ investigation included adults aged at least 40 years with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with prior dementia diagnoses were excluded. Their analysis found the risk of incident dementia to be comparable between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), non-TNFi bDMARDs (HR, 0.76; 95% CI, 0.70-0.83), and tsDMARDs (HR, 0.69; 95% CI, 0.53-0.90), with csDMARDs as the referent. A second subgroup analysis looking at patients with prior methotrexate use who were taking bDMARDs or tsDMARDs revealed similar decreases in risk of incident dementia, compared with patients taking bDMARDs or tsDMARDs along with methotrexate at baseline.

“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Dr. Sattui said in the interview. “Despite initial observational data that showed some signal for improvement, no benefit was observed in either of the RCTs. Other agents with possible anti-inflammatory effects and more benign profiles, such as curcumin, are being studied. There are also ongoing trials looking into the use of JAK [Janus kinase] inhibitors or [interleukin]-1 inhibition in dementia.”

He added: “There is a need to better study the association between cognition and disease activity, as well as treat-to-target strategies, prospectively in patients with RA. It is important to also acknowledge that any of these findings might be just specific for RA, so extrapolation to non-RA individuals might be limited.”

In commenting on the findings of the study, Rishi J. Desai, PhD, assistant professor of medicine in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston, said that “superior inflammation control with biologics or targeted DMARDs is an interesting hypothesis explaining the observed findings. It merits further investigation and replication in diverse populations.” He added: “It should be noted that a key challenge in evaluating this hypothesis using insurance claims data is unavailability of some important factors such as socioeconomic status and patient frailty. These may be driving treatment selection between conventional DMARDs, which are cheaper with more benign adverse-event profiles, and biologic or targeted DMARDs, which are more expensive with a less favorable adverse-event profile.”
 

Prior research

Several studies have investigated the effect of DMARDs, including bDMARDs like tumor necrosis factor inhibitors, on incident dementia in patients with RA.

Among this research is a study by Dr. Desai and colleagues that looked at comparative risk of AD and related dementia in 22,569 Medicare beneficiaries receiving tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors in comparison with abatacept (a T-cell activation inhibitor). No differentiating risk associations were found in this cohort study.

Other past studies include:

• A study comparing about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in dementia development among RA patients receiving DMARDs. The effect was dose dependent, greater with high cumulative dosages, and was found in both men and women and in subgroups younger and older than 65 years.
• A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased risk for AD through a mechanism involving TNF. The risk for AD in patients was lowered by treatment with etanercept, adalimumab, infliximab, or methotrexate, with larger reductions observed in younger patients than in older patients receiving TNF blockers.
• A propensity score–matched retrospective cohort study in 2,510 U.S. veterans with RA found that use of a TNF inhibitor reduced the risk of dementia by 36%, compared with control patients (HR, 0.64; 95% CI, 0.52-0.80), and the effect was consistent over 5-20 years post RA diagnosis.
• In a retrospective, multinational, matched, case-control study of patients older than 50 years with RA, prior methotrexate use was associated with lower dementia risk (OR, 0.71; 95% CI, 0.52-0.98). Use of methotrexate longer than 4 years demonstrated the lowest dementia risk (odds ratio, 0.37; 95% CI, 0.17-0.79).

These past studies, Dr. Sattui and colleagues pointed out, have multiple shortcomings, including case-control design, different definitions of exposure or outcomes, and inadequate control of confounders, underscoring the need for more rigorous studies.

Several authors of the CMS claims study disclosed research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Dr. Desai disclosed that he has received funding from the National Institute on Aging for drug repurposing studies of dementia.

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Brain wave recordings obtained during cardiopulmonary resuscitation (CPR) offer support to near-death experiences subjectively reported by some people who survive cardiac arrest, according to a novel new study.

“These recalled experiences and brain wave changes may be the first signs of the so-called ‘near-death’ experience, and we have captured them for the first time in a large study,” lead investigator Sam Parnia, MD, PhD, with NYU Langone Health, said in a news release.

Identifying measurable electrical signs of lucid and heightened brain activity during CPR, coupled with stories of recalled near-death experiences, suggests that the human sense of self and consciousness, much like other biological body functions, may not stop completely around the time of death, Dr. Parnia added.

He presented the findings Nov. 6 at a resuscitation science symposium at the American Heart Association scientific sessions.
 

The AWARE II study

“For years, some people in cardiac arrest have reported being lucid, often with a heightened sense of consciousness, while seemingly unconscious and on the brink of death,” Dr. Parnia noted in an interview.

“Yet, no one’s ever be able to prove it and a lot of people have dismissed these experiences, thinking it’s all just a trick on the brain,” Dr. Parnia said.

In a first-of-its-kind study, Dr. Parnia and colleagues examined consciousness and its underlying electrocortical biomarkers during CPR for in-hospital cardiac arrest (IHCA).

They incorporated independent audiovisual testing of awareness with continuous real-time EEG and cerebral oxygenation (rSO₂) monitoring into CPR.

Only 53 of the 567 IHCA patients survived (9.3%). Among the 28 (52.8%) IHCA survivors who completed interviews, 11 (39.3%) reported unique, lucid experiences during resuscitation.

These experiences included a perception of separation from one’s body, observing events without pain or distress, and an awareness and meaningful evaluation of life, including of their actions, intentions, and thoughts toward others.

“These lucid experiences of death are not hallucinations or delusions. They cannot be considered a trick of a disordered or dying brain, but rather a unique human experience that emerges on the brink of death,” Dr. Parnia said. 

And what’s “fascinating,” he added, is that despite marked cerebral ischemia (mean regional oxygen saturation [rSO₂]  43%), near-normal/physiologic EEG activity (gamma, delta, theta, alpha, and beta rhythms) consistent with consciousness and a possible resumption of a network-level of cognitive and neuronal activity emerged for as long as 35-60 minutes into CPR.

Some of these brain waves normally occur when people are conscious and performing higher mental functions, including thinking, memory retrieval, and conscious perception, he said.
 

‘Seismic shift’ in understanding of death

This is the first time such biomarkers of consciousness have been identified during cardiac arrest and CPR, Dr. Parnia said.

He said further study is needed to more precisely define biomarkers of what is considered to be clinical consciousness and the recalled experience of death, and to monitor the long-term psychological effects of resuscitation after cardiac arrest.

“Our understanding of death has gone through a seismic shift in the last few years,” he said.

“The biological discoveries around death and the postmortem period are completely different to the social conventions that we have about death. That is, we perceive of death as being the end, but actually what we’re finding is that brain cells don’t die immediately. They die very slowly over many hours of time,” Dr. Parnia noted.

Reached for comment, Ajmal Zemmar, MD, PhD, of University of Louisville (Ky.), noted that several studies, including this one, “challenge the traditional way that we think of death – that when the heart stops beating that’s when we die.”

The observation that during cardiac arrest and CPR, the brain waves are still normal for up to an hour is “fairly remarkable,” Dr. Zemmar told this news organization.

“However, whether there is conscious perception or not is very hard to answer,” he cautioned. 

“This type of research tries to bridge the objective EEG recordings with the subjective description you get from the patient, but it’s hard to know when conscious perception stops,” he said.

Funding and support for the study were provided by NYU Langone Health, The John Templeton Foundation, and the UK Resuscitation Council, and National Institutes for Health Research. Dr. Parnia and Dr. Zemmar reported no relevant financial relationships.

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

Sacral nerve stimulation (SNS) is a therapeutic procedure that could be used to help women with sexual dysfunction. However, the benefits of this method in this indication should still be reviewed in high-quality studies with sexual function as the primary endpoint, Erik Allemeyer, MD, PhD, a proctologist at the Niels Stensen Clinics in Georgsmarienhütte, Germany, and colleagues wrote in a recent journal article.

The World Health Organization defines sexual health as physical, emotional, mental, and social well-being in relation to sexuality. There are extensive investigations that verify the considerable importance of sexual function on a person’s quality of life. It therefore follows that therapy may be required if an individual is experiencing sexual dysfunction.

According to the authors, there are diverse data on the frequency of sexual dysfunction in women, in part because of heterogeneous definitions. The prevalence ranges between 26% and 91%. The estimated prevalence of orgasm difficulties in particular ranges from 16% to 25%. Sexual dysfunction can therefore be said to be a clinically significant problem.

It was recently discovered that SNS, which has only been used for other conditions so far, could also be an option for women with sexual dysfunction. According to Dr. Allemeyer and coauthors, SNS was first described in 1988 as a therapeutic alternative for patients with neurogenic bladder and has been approved in Europe since 1994. As a minimally invasive therapy for urge incontinence, idiopathic pelvic pain, and for nonobstructive urinary retention, SNS can now be used to treat a wide spectrum of conditions in urology and urogynecology. After the successful stimulation treatment of fecal incontinence was first described in 1995, the procedure has also been used in coloproctology.
 

Tested before implantation

In SNS, sacral nerve roots (S3 and S4) are permanently stimulated via a percutaneously implanted electrode. At first, the effect is reviewed using a test electrode and an external impulse generator over a period of a few weeks. Only if the test stimulation significantly alleviates symptoms can the indication for full implantation be issued, wrote the authors.

The positive effects on sexual function could be seen, even in the early years of stimulation therapy, when it was used for urinary and fecal incontinence as well as for idiopathic pelvic pain, they added. They have now summarized and discussed the current state of research on the potential effects of SNS on women’s sexual function in a literature review.
 

Systematic study analysis

To do this, they analyzed 16 studies, which included a total of 662 women, that reviewed the effect of SNS on sexual function when the treatment was being used in other indications. The overwhelming majority of data relates to urologic indications for SNS (such as overactive bladder, chronic retention, and idiopathic pelvic pain). In contrast, the SNS indication was rarely issued for fecal incontinence (9.1% of SNS indications or 61 patients). The most often used tool to assess the effect is the validated Female Sexual Function Index. The indicators covered in this index are “desire,” “arousal,” “lubrication,” “orgasm,” and “satisfaction.”

According to Dr. Allemeyer and coauthors, the analysis revealed evidence of significantly improved sexual function. It was unclear, however, whether this improvement was a primary or secondary effect of the SNS. All the original works and reviews expressly indicated that there was no proof of a primary effect of SNS on sexual function.

The mode of action of SNS and the immediate anatomic and physiologic link between the functions of urination, urinary incontinence, pelvic pain, fecal incontinence, and sexual function suggest a possible primary effect of SNS on sexual function, wrote the authors. However, no investigations use sexual function as the primary outcome parameter of SNS. This outcome should be reviewed in high-quality studies with sexual function as the primary endpoint.
 

An experimental therapy

According to Dr. Allemeyer and colleagues, two practical conclusions can be drawn from the study data available to date:

A possible primary effect of SNS on sexual function should be reviewed in high-quality, prospective studies that include detailed analyses of the different aspects of sexual dysfunction in both sexes.

An offer for trial-based SNS for sexual dysfunction should be made only at experienced sites with a multidisciplinary team of sex therapists and medical specialists and only after available therapy options have been exhausted and initially only within systematic studies.

This article was translated from Univadis Germany and a version appeared on Medscape.com.

Sacral nerve stimulation (SNS) is a therapeutic procedure that could be used to help women with sexual dysfunction. However, the benefits of this method in this indication should still be reviewed in high-quality studies with sexual function as the primary endpoint, Erik Allemeyer, MD, PhD, a proctologist at the Niels Stensen Clinics in Georgsmarienhütte, Germany, and colleagues wrote in a recent journal article.

The World Health Organization defines sexual health as physical, emotional, mental, and social well-being in relation to sexuality. There are extensive investigations that verify the considerable importance of sexual function on a person’s quality of life. It therefore follows that therapy may be required if an individual is experiencing sexual dysfunction.

According to the authors, there are diverse data on the frequency of sexual dysfunction in women, in part because of heterogeneous definitions. The prevalence ranges between 26% and 91%. The estimated prevalence of orgasm difficulties in particular ranges from 16% to 25%. Sexual dysfunction can therefore be said to be a clinically significant problem.

It was recently discovered that SNS, which has only been used for other conditions so far, could also be an option for women with sexual dysfunction. According to Dr. Allemeyer and coauthors, SNS was first described in 1988 as a therapeutic alternative for patients with neurogenic bladder and has been approved in Europe since 1994. As a minimally invasive therapy for urge incontinence, idiopathic pelvic pain, and for nonobstructive urinary retention, SNS can now be used to treat a wide spectrum of conditions in urology and urogynecology. After the successful stimulation treatment of fecal incontinence was first described in 1995, the procedure has also been used in coloproctology.
 

Tested before implantation

In SNS, sacral nerve roots (S3 and S4) are permanently stimulated via a percutaneously implanted electrode. At first, the effect is reviewed using a test electrode and an external impulse generator over a period of a few weeks. Only if the test stimulation significantly alleviates symptoms can the indication for full implantation be issued, wrote the authors.

The positive effects on sexual function could be seen, even in the early years of stimulation therapy, when it was used for urinary and fecal incontinence as well as for idiopathic pelvic pain, they added. They have now summarized and discussed the current state of research on the potential effects of SNS on women’s sexual function in a literature review.
 

Systematic study analysis

To do this, they analyzed 16 studies, which included a total of 662 women, that reviewed the effect of SNS on sexual function when the treatment was being used in other indications. The overwhelming majority of data relates to urologic indications for SNS (such as overactive bladder, chronic retention, and idiopathic pelvic pain). In contrast, the SNS indication was rarely issued for fecal incontinence (9.1% of SNS indications or 61 patients). The most often used tool to assess the effect is the validated Female Sexual Function Index. The indicators covered in this index are “desire,” “arousal,” “lubrication,” “orgasm,” and “satisfaction.”

According to Dr. Allemeyer and coauthors, the analysis revealed evidence of significantly improved sexual function. It was unclear, however, whether this improvement was a primary or secondary effect of the SNS. All the original works and reviews expressly indicated that there was no proof of a primary effect of SNS on sexual function.

The mode of action of SNS and the immediate anatomic and physiologic link between the functions of urination, urinary incontinence, pelvic pain, fecal incontinence, and sexual function suggest a possible primary effect of SNS on sexual function, wrote the authors. However, no investigations use sexual function as the primary outcome parameter of SNS. This outcome should be reviewed in high-quality studies with sexual function as the primary endpoint.
 

An experimental therapy

According to Dr. Allemeyer and colleagues, two practical conclusions can be drawn from the study data available to date:

A possible primary effect of SNS on sexual function should be reviewed in high-quality, prospective studies that include detailed analyses of the different aspects of sexual dysfunction in both sexes.

An offer for trial-based SNS for sexual dysfunction should be made only at experienced sites with a multidisciplinary team of sex therapists and medical specialists and only after available therapy options have been exhausted and initially only within systematic studies.

This article was translated from Univadis Germany and a version appeared on Medscape.com.

Sacral nerve stimulation (SNS) is a therapeutic procedure that could be used to help women with sexual dysfunction. However, the benefits of this method in this indication should still be reviewed in high-quality studies with sexual function as the primary endpoint, Erik Allemeyer, MD, PhD, a proctologist at the Niels Stensen Clinics in Georgsmarienhütte, Germany, and colleagues wrote in a recent journal article.

The World Health Organization defines sexual health as physical, emotional, mental, and social well-being in relation to sexuality. There are extensive investigations that verify the considerable importance of sexual function on a person’s quality of life. It therefore follows that therapy may be required if an individual is experiencing sexual dysfunction.

According to the authors, there are diverse data on the frequency of sexual dysfunction in women, in part because of heterogeneous definitions. The prevalence ranges between 26% and 91%. The estimated prevalence of orgasm difficulties in particular ranges from 16% to 25%. Sexual dysfunction can therefore be said to be a clinically significant problem.

It was recently discovered that SNS, which has only been used for other conditions so far, could also be an option for women with sexual dysfunction. According to Dr. Allemeyer and coauthors, SNS was first described in 1988 as a therapeutic alternative for patients with neurogenic bladder and has been approved in Europe since 1994. As a minimally invasive therapy for urge incontinence, idiopathic pelvic pain, and for nonobstructive urinary retention, SNS can now be used to treat a wide spectrum of conditions in urology and urogynecology. After the successful stimulation treatment of fecal incontinence was first described in 1995, the procedure has also been used in coloproctology.
 

Tested before implantation

In SNS, sacral nerve roots (S3 and S4) are permanently stimulated via a percutaneously implanted electrode. At first, the effect is reviewed using a test electrode and an external impulse generator over a period of a few weeks. Only if the test stimulation significantly alleviates symptoms can the indication for full implantation be issued, wrote the authors.

The positive effects on sexual function could be seen, even in the early years of stimulation therapy, when it was used for urinary and fecal incontinence as well as for idiopathic pelvic pain, they added. They have now summarized and discussed the current state of research on the potential effects of SNS on women’s sexual function in a literature review.
 

Systematic study analysis

To do this, they analyzed 16 studies, which included a total of 662 women, that reviewed the effect of SNS on sexual function when the treatment was being used in other indications. The overwhelming majority of data relates to urologic indications for SNS (such as overactive bladder, chronic retention, and idiopathic pelvic pain). In contrast, the SNS indication was rarely issued for fecal incontinence (9.1% of SNS indications or 61 patients). The most often used tool to assess the effect is the validated Female Sexual Function Index. The indicators covered in this index are “desire,” “arousal,” “lubrication,” “orgasm,” and “satisfaction.”

According to Dr. Allemeyer and coauthors, the analysis revealed evidence of significantly improved sexual function. It was unclear, however, whether this improvement was a primary or secondary effect of the SNS. All the original works and reviews expressly indicated that there was no proof of a primary effect of SNS on sexual function.

The mode of action of SNS and the immediate anatomic and physiologic link between the functions of urination, urinary incontinence, pelvic pain, fecal incontinence, and sexual function suggest a possible primary effect of SNS on sexual function, wrote the authors. However, no investigations use sexual function as the primary outcome parameter of SNS. This outcome should be reviewed in high-quality studies with sexual function as the primary endpoint.
 

An experimental therapy

According to Dr. Allemeyer and colleagues, two practical conclusions can be drawn from the study data available to date:

A possible primary effect of SNS on sexual function should be reviewed in high-quality, prospective studies that include detailed analyses of the different aspects of sexual dysfunction in both sexes.

An offer for trial-based SNS for sexual dysfunction should be made only at experienced sites with a multidisciplinary team of sex therapists and medical specialists and only after available therapy options have been exhausted and initially only within systematic studies.

This article was translated from Univadis Germany and a version appeared on Medscape.com.

An investigational drug that targets abnormal clumps of alpha-synuclein protein in the gut safely reduced constipation in patients with Parkinson’s disease (PD) in a new study.

The findings are based on 135 patients who completed 7-25 days of treatment with a daily oral dose of the drug, ENT-01, or a placebo. Complete spontaneous bowel movements (CSBMs), the primary efficacy endpoint, increased from a mean of 0.7 per week to 3.2 in individuals who took ENT-01 versus 1.2 in the placebo group.

The phase 2, multicenter, randomized trial showed that the drug “is safe and that it rapidly normalized bowel function in a dose-dependent fashion, with an effect that seems to persist for several weeks beyond the treatment period,” the researchers wrote in their paper on the research, which was published in Annals of Internal Medicine.

The researchers hypothesized that displacing aggregated alpha-synuclein from nerve cells in the gastrointestinal tract may also “slow progression of neurologic symptoms” in patients with PD by arresting the abnormal development of alpha-nucleic aggregates in the brain.

Denise Barbut, MD, cofounder, president and chief medical officer of Enterin, the company developing ENT-01, said the next step is another phase 2 trial to determine whether the drug reverses dementia or psychosis in patients with PD, before conducting a phase 3 study.

“We want to treat all nonmotor symptoms of Parkinson’s disease, not just constipation,” she said.
 

Constipation is an early PD symptom

Constipation is a common and persistent symptom of PD that often emerges years earlier than other symptoms such as motor deficits. Recent research has linked it to aggregates of alpha-synuclein that bind to cells in the enteric nervous system and may spread to the brain via the vagus nerve.

According to the researchers, ENT-01, a synthetic derivative of the antimicrobial compound squalamine, improves neural signaling in the gut by displacing alpha-synuclein aggregates.

In their double-blinded study, patients were randomized 3:1 to receive ENT-01 or a placebo and stratified by constipation severity to one of two starting doses: 75 mg or three placebo pills or 150 mg or six placebo pills. Doses increased until a patient reached a “prokinetic” dose, a maximum of 250 mg or 10 placebo pills, or the individual’s tolerability limit.

Dosing was fixed for the remainder of the 25 days, after which all patients took a placebo for 2 weeks followed by a 4-week washout.

In addition to more CSBMs, the treatment group had greater improvements in secondary endpoints of weekly spontaneous bowel movements (P = .002), better stool consistency (P < .001), improved ease of passage (P = .006), and less laxative use (P = .041).

There were no significant differences between the groups in scores on the Patient Assessment of Constipation Symptoms or the Patient Assessment of Constipation Quality of Life.

No deaths occurred, and there were no serious adverse events attributed to ENT-01. However, adverse events occurred in 61 (65.6%) of patients who took the drug versus 27 (47.4%) of those who took a placebo.

The most common problems were nausea, experienced by 32 (34%) in the ENT-01 group and 3 (5.3%) in the placebo group, and diarrhea, which occurred in 18 (9.4%) of those in the ENT-01 group and three (5.3%) who took the placebo.

Of 93 patients randomized to the drug (25.8%), 24 discontinued treatment before therapy ended, mostly because of nausea or diarrhea. That compared with 8 of 57 (14.1%) patients in the placebo group who stopped taking their pills before the end of the therapy period.

The researchers suggested that nausea and diarrhea might be alleviated by more gradual dosing escalation and the use of antinausea medication.

Dr. Barbut noted that a previous open-label trial of 50 patients with PD showed that ENT-01 acts locally in the gastrointestinal tract, which means it would not be absorbed into the bloodstream or interfere with other medications.
 

Targeting the underlying disease

Researchers noted that, in small subsets of patients with dementia or psychosis, greater improvements in those symptoms occurred among those who took ENT-01 versus those who took a placebo.

According to the study, among 11 patients with psychosis, average scores on the Scale for the Assessment of Positive Symptoms adapted for PD dropped from 6.5 to 1.8 on a 45-point scale at the end of treatment in the ENT-01 group (n = 5) and from 6.3 to 3.4 in the placebo group (n = 6).

In 28 patients with dementia, scores on the Mini-Mental State Examination improved by 2.4 points on a 30-point scale, from 24.1 to 26.5, during the treatment period for the ENT-01 group (n = 14) versus an improvement of 0.9 points, from 24.8 to 25.7, in the placebo group (n = 14).

The researchers said the findings must be evaluated in future trials dedicated to studying ENT-01’s effects on PD-related psychosis and dementia.

An investigational drug that targets abnormal clumps of alpha-synuclein protein in the gut safely reduced constipation in patients with Parkinson’s disease (PD) in a new study.

The findings are based on 135 patients who completed 7-25 days of treatment with a daily oral dose of the drug, ENT-01, or a placebo. Complete spontaneous bowel movements (CSBMs), the primary efficacy endpoint, increased from a mean of 0.7 per week to 3.2 in individuals who took ENT-01 versus 1.2 in the placebo group.

The phase 2, multicenter, randomized trial showed that the drug “is safe and that it rapidly normalized bowel function in a dose-dependent fashion, with an effect that seems to persist for several weeks beyond the treatment period,” the researchers wrote in their paper on the research, which was published in Annals of Internal Medicine.

The researchers hypothesized that displacing aggregated alpha-synuclein from nerve cells in the gastrointestinal tract may also “slow progression of neurologic symptoms” in patients with PD by arresting the abnormal development of alpha-nucleic aggregates in the brain.

Denise Barbut, MD, cofounder, president and chief medical officer of Enterin, the company developing ENT-01, said the next step is another phase 2 trial to determine whether the drug reverses dementia or psychosis in patients with PD, before conducting a phase 3 study.

“We want to treat all nonmotor symptoms of Parkinson’s disease, not just constipation,” she said.
 

Constipation is an early PD symptom

Constipation is a common and persistent symptom of PD that often emerges years earlier than other symptoms such as motor deficits. Recent research has linked it to aggregates of alpha-synuclein that bind to cells in the enteric nervous system and may spread to the brain via the vagus nerve.

According to the researchers, ENT-01, a synthetic derivative of the antimicrobial compound squalamine, improves neural signaling in the gut by displacing alpha-synuclein aggregates.

In their double-blinded study, patients were randomized 3:1 to receive ENT-01 or a placebo and stratified by constipation severity to one of two starting doses: 75 mg or three placebo pills or 150 mg or six placebo pills. Doses increased until a patient reached a “prokinetic” dose, a maximum of 250 mg or 10 placebo pills, or the individual’s tolerability limit.

Dosing was fixed for the remainder of the 25 days, after which all patients took a placebo for 2 weeks followed by a 4-week washout.

In addition to more CSBMs, the treatment group had greater improvements in secondary endpoints of weekly spontaneous bowel movements (P = .002), better stool consistency (P < .001), improved ease of passage (P = .006), and less laxative use (P = .041).

There were no significant differences between the groups in scores on the Patient Assessment of Constipation Symptoms or the Patient Assessment of Constipation Quality of Life.

No deaths occurred, and there were no serious adverse events attributed to ENT-01. However, adverse events occurred in 61 (65.6%) of patients who took the drug versus 27 (47.4%) of those who took a placebo.

The most common problems were nausea, experienced by 32 (34%) in the ENT-01 group and 3 (5.3%) in the placebo group, and diarrhea, which occurred in 18 (9.4%) of those in the ENT-01 group and three (5.3%) who took the placebo.

Of 93 patients randomized to the drug (25.8%), 24 discontinued treatment before therapy ended, mostly because of nausea or diarrhea. That compared with 8 of 57 (14.1%) patients in the placebo group who stopped taking their pills before the end of the therapy period.

The researchers suggested that nausea and diarrhea might be alleviated by more gradual dosing escalation and the use of antinausea medication.

Dr. Barbut noted that a previous open-label trial of 50 patients with PD showed that ENT-01 acts locally in the gastrointestinal tract, which means it would not be absorbed into the bloodstream or interfere with other medications.
 

Targeting the underlying disease

Researchers noted that, in small subsets of patients with dementia or psychosis, greater improvements in those symptoms occurred among those who took ENT-01 versus those who took a placebo.

According to the study, among 11 patients with psychosis, average scores on the Scale for the Assessment of Positive Symptoms adapted for PD dropped from 6.5 to 1.8 on a 45-point scale at the end of treatment in the ENT-01 group (n = 5) and from 6.3 to 3.4 in the placebo group (n = 6).

In 28 patients with dementia, scores on the Mini-Mental State Examination improved by 2.4 points on a 30-point scale, from 24.1 to 26.5, during the treatment period for the ENT-01 group (n = 14) versus an improvement of 0.9 points, from 24.8 to 25.7, in the placebo group (n = 14).

The researchers said the findings must be evaluated in future trials dedicated to studying ENT-01’s effects on PD-related psychosis and dementia.

An investigational drug that targets abnormal clumps of alpha-synuclein protein in the gut safely reduced constipation in patients with Parkinson’s disease (PD) in a new study.

The findings are based on 135 patients who completed 7-25 days of treatment with a daily oral dose of the drug, ENT-01, or a placebo. Complete spontaneous bowel movements (CSBMs), the primary efficacy endpoint, increased from a mean of 0.7 per week to 3.2 in individuals who took ENT-01 versus 1.2 in the placebo group.

The phase 2, multicenter, randomized trial showed that the drug “is safe and that it rapidly normalized bowel function in a dose-dependent fashion, with an effect that seems to persist for several weeks beyond the treatment period,” the researchers wrote in their paper on the research, which was published in Annals of Internal Medicine.

The researchers hypothesized that displacing aggregated alpha-synuclein from nerve cells in the gastrointestinal tract may also “slow progression of neurologic symptoms” in patients with PD by arresting the abnormal development of alpha-nucleic aggregates in the brain.

Denise Barbut, MD, cofounder, president and chief medical officer of Enterin, the company developing ENT-01, said the next step is another phase 2 trial to determine whether the drug reverses dementia or psychosis in patients with PD, before conducting a phase 3 study.

“We want to treat all nonmotor symptoms of Parkinson’s disease, not just constipation,” she said.
 

Constipation is an early PD symptom

Constipation is a common and persistent symptom of PD that often emerges years earlier than other symptoms such as motor deficits. Recent research has linked it to aggregates of alpha-synuclein that bind to cells in the enteric nervous system and may spread to the brain via the vagus nerve.

According to the researchers, ENT-01, a synthetic derivative of the antimicrobial compound squalamine, improves neural signaling in the gut by displacing alpha-synuclein aggregates.

In their double-blinded study, patients were randomized 3:1 to receive ENT-01 or a placebo and stratified by constipation severity to one of two starting doses: 75 mg or three placebo pills or 150 mg or six placebo pills. Doses increased until a patient reached a “prokinetic” dose, a maximum of 250 mg or 10 placebo pills, or the individual’s tolerability limit.

Dosing was fixed for the remainder of the 25 days, after which all patients took a placebo for 2 weeks followed by a 4-week washout.

In addition to more CSBMs, the treatment group had greater improvements in secondary endpoints of weekly spontaneous bowel movements (P = .002), better stool consistency (P < .001), improved ease of passage (P = .006), and less laxative use (P = .041).

There were no significant differences between the groups in scores on the Patient Assessment of Constipation Symptoms or the Patient Assessment of Constipation Quality of Life.

No deaths occurred, and there were no serious adverse events attributed to ENT-01. However, adverse events occurred in 61 (65.6%) of patients who took the drug versus 27 (47.4%) of those who took a placebo.

The most common problems were nausea, experienced by 32 (34%) in the ENT-01 group and 3 (5.3%) in the placebo group, and diarrhea, which occurred in 18 (9.4%) of those in the ENT-01 group and three (5.3%) who took the placebo.

Of 93 patients randomized to the drug (25.8%), 24 discontinued treatment before therapy ended, mostly because of nausea or diarrhea. That compared with 8 of 57 (14.1%) patients in the placebo group who stopped taking their pills before the end of the therapy period.

The researchers suggested that nausea and diarrhea might be alleviated by more gradual dosing escalation and the use of antinausea medication.

Dr. Barbut noted that a previous open-label trial of 50 patients with PD showed that ENT-01 acts locally in the gastrointestinal tract, which means it would not be absorbed into the bloodstream or interfere with other medications.
 

Targeting the underlying disease

Researchers noted that, in small subsets of patients with dementia or psychosis, greater improvements in those symptoms occurred among those who took ENT-01 versus those who took a placebo.

According to the study, among 11 patients with psychosis, average scores on the Scale for the Assessment of Positive Symptoms adapted for PD dropped from 6.5 to 1.8 on a 45-point scale at the end of treatment in the ENT-01 group (n = 5) and from 6.3 to 3.4 in the placebo group (n = 6).

In 28 patients with dementia, scores on the Mini-Mental State Examination improved by 2.4 points on a 30-point scale, from 24.1 to 26.5, during the treatment period for the ENT-01 group (n = 14) versus an improvement of 0.9 points, from 24.8 to 25.7, in the placebo group (n = 14).

The researchers said the findings must be evaluated in future trials dedicated to studying ENT-01’s effects on PD-related psychosis and dementia.

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

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

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

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

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

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

Researchers have identified a set of 42 genes that are associated with dyslexia, based on data from approximately 50,000 dyslexic individuals and 1 million controls.

Dyslexia occurs in 5%-17% of the general population, depending on the diagnostic criteria, and has been linked with speech and language disorders, as well as ADHD, Catherine Doust, PhD, of the University of Edinburgh and colleagues wrote.

However, previous studies of the genetics of dyslexia are limited, corresponding author Michelle Luciano, PhD, said in an interview. “So much progress has been made in understanding the genetics of behavior and health, but only a small genomewide study of dyslexia existed before ours.”

Currently, genetic testing for dyslexia alone is not done.

“You couldn’t order a genetic test for dyslexia unless it were part of another genetic panel,” according to Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y.

There are also known associations with some genes and autism, but none are definitive, and testing requires a workup of which a genetic panel may be a part. Such tests are expensive, and rarely covered by insurance, the pediatrician explained. 

Experts recommend genetic screening for every child with developmental delay, but most insurance won’t cover it, Dr. Lessin continued.

In the new genomewide association study published in Nature Genetics, the researchers reviewed data from 51,800 adults aged 18 years and older with a self-reported dyslexia diagnosis and 1,087,070 controls. All study participants are enrolled in ongoing research with 23andMe, the personal genetics company.

The researchers investigated the genetic correlations with reading and related skills and evaluated evidence for genes previously associated with dyslexia. The mean ages of the dyslexia cases and controls were 49.6 years and 51.7 years, respectively.

The researchers identified 42 independent genetic variants (genomewide significant loci) associated with dyslexia; 15 of these loci were in genes previously associated with cognitive ability and educational attainment, and 27 were newly identified as specifically associated with dyslexia. The researchers further determined that 12 of the newly identified genes were associated with proficiency in reading and spelling in English and European languages, and 1 in a Chinese-language population.

A polygenic risk score is a way to characterize an individual’s risk of developing a disease, based on the total number of genetic changes related to the disease; the researchers used this score to validate their results. Dyslexia polygenic scores were used to predict reading and spelling in additional population-based and reading disorder–enriched samples outside of the study population; these genetic measures explained up to 6% of variance in reading traits, the researchers noted. Ultimately, these scores may be a tool to help identify children with a predisposition for dyslexia so reading skills support can begin early.

The researchers also found that many of the genes associated with dyslexia are also associated with ADHD, (24% of dyslexia patients reporting ADHD vs. 9% of controls), and with a moderate correlation, which suggests possible shared genetic components for deficits in working memory and attention.

The study findings were limited by the inability to prove causality, and by the potential bias in the study sample, but were strengthened by the large study population, the researchers noted.
 

Potential implications for reading and spelling

“We were surprised that none of the previous dyslexia candidate genes were genomewide significant in our study; all of our discoveries were in new genes that had not been previously implicated in dyslexia,” Dr. Luciano said in an interview. “Some of these genes have been found to be associated with general cognitive ability, but most were novel and may represent genes specifically related to cognitive processes dominant in reading and spelling.

“We were also surprised that there was little genetic correlation (or overlap) with brain MRI variables, given that brain regions have been linked to reading skill. This suggests that the link is environmental in origin,” she added.

“Our results do not directly feed into clinical practice,” said Dr. Luciano. However, “the moderate genetic overlap with ADHD suggests that broader assessments of behavior are important when a child presents with dyslexia, as co-occurrence with other conditions might influence the intervention chosen. Asking about family history of dyslexia might also help in identification.

With more research, genetic studies may find a place in the clinical setting, said Dr. Luciano.  

“As genomewide association studies become larger and the findings more stable, genetic information might be used as an adjunct to what is known about the child’s environment and their performance on standardized tests of reading. The key advantage of genetic information is that it could allow much earlier identification of children who would benefit from extra learning support,” she said.

More research is needed to understand the interaction between genes and the environment, Dr. Luciano said. “It is essential that we understand what environmental learning support can minimize genetic predisposition to dyslexia.”
 

Too soon for clinical utility

The study findings are an important foundation for additional research, but not yet clinically useful, Dr. Lessin said in an interview.

“Dyslexia is a tough diagnosis,” that requires assessment by a developmental pediatrician or a pediatric neurologist and these specialists are often not accessible to many parents, Dr. Lessin noted.

In the current study, the researchers found a number of genes potentially associated with dyslexia, but the study does not prove causality, he emphasized. The findings simply mean that some of these genes may have something to do with dyslexia, and further research might identify a genetic cause.

“No one is going to make a diagnosis of dyslexia based on genes just yet,” said Dr. Lessin. In the meantime, clinicians should be aware that good research is being conducted, and that the genetic foundations for dyslexia are being explored.

Lead author Dr. Doust and corresponding author Dr. Luciano had no financial conflicts to disclose. Several coauthors disclosed support from the Max Planck Society (Germany), the National Natural Science Foundation of China, Funds for Humanities and Social Sciences Research of the Ministry of Education, and General Project of Shaanxi Natural Science Basic Research Program. Two coauthors are employed by and hold stock or stock options in 23andMe. Dr. Lessin had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

Researchers have identified a set of 42 genes that are associated with dyslexia, based on data from approximately 50,000 dyslexic individuals and 1 million controls.

Dyslexia occurs in 5%-17% of the general population, depending on the diagnostic criteria, and has been linked with speech and language disorders, as well as ADHD, Catherine Doust, PhD, of the University of Edinburgh and colleagues wrote.

However, previous studies of the genetics of dyslexia are limited, corresponding author Michelle Luciano, PhD, said in an interview. “So much progress has been made in understanding the genetics of behavior and health, but only a small genomewide study of dyslexia existed before ours.”

Currently, genetic testing for dyslexia alone is not done.

“You couldn’t order a genetic test for dyslexia unless it were part of another genetic panel,” according to Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y.

There are also known associations with some genes and autism, but none are definitive, and testing requires a workup of which a genetic panel may be a part. Such tests are expensive, and rarely covered by insurance, the pediatrician explained. 

Experts recommend genetic screening for every child with developmental delay, but most insurance won’t cover it, Dr. Lessin continued.

In the new genomewide association study published in Nature Genetics, the researchers reviewed data from 51,800 adults aged 18 years and older with a self-reported dyslexia diagnosis and 1,087,070 controls. All study participants are enrolled in ongoing research with 23andMe, the personal genetics company.

The researchers investigated the genetic correlations with reading and related skills and evaluated evidence for genes previously associated with dyslexia. The mean ages of the dyslexia cases and controls were 49.6 years and 51.7 years, respectively.

The researchers identified 42 independent genetic variants (genomewide significant loci) associated with dyslexia; 15 of these loci were in genes previously associated with cognitive ability and educational attainment, and 27 were newly identified as specifically associated with dyslexia. The researchers further determined that 12 of the newly identified genes were associated with proficiency in reading and spelling in English and European languages, and 1 in a Chinese-language population.

A polygenic risk score is a way to characterize an individual’s risk of developing a disease, based on the total number of genetic changes related to the disease; the researchers used this score to validate their results. Dyslexia polygenic scores were used to predict reading and spelling in additional population-based and reading disorder–enriched samples outside of the study population; these genetic measures explained up to 6% of variance in reading traits, the researchers noted. Ultimately, these scores may be a tool to help identify children with a predisposition for dyslexia so reading skills support can begin early.

The researchers also found that many of the genes associated with dyslexia are also associated with ADHD, (24% of dyslexia patients reporting ADHD vs. 9% of controls), and with a moderate correlation, which suggests possible shared genetic components for deficits in working memory and attention.

The study findings were limited by the inability to prove causality, and by the potential bias in the study sample, but were strengthened by the large study population, the researchers noted.
 

Potential implications for reading and spelling

“We were surprised that none of the previous dyslexia candidate genes were genomewide significant in our study; all of our discoveries were in new genes that had not been previously implicated in dyslexia,” Dr. Luciano said in an interview. “Some of these genes have been found to be associated with general cognitive ability, but most were novel and may represent genes specifically related to cognitive processes dominant in reading and spelling.

“We were also surprised that there was little genetic correlation (or overlap) with brain MRI variables, given that brain regions have been linked to reading skill. This suggests that the link is environmental in origin,” she added.

“Our results do not directly feed into clinical practice,” said Dr. Luciano. However, “the moderate genetic overlap with ADHD suggests that broader assessments of behavior are important when a child presents with dyslexia, as co-occurrence with other conditions might influence the intervention chosen. Asking about family history of dyslexia might also help in identification.

With more research, genetic studies may find a place in the clinical setting, said Dr. Luciano.  

“As genomewide association studies become larger and the findings more stable, genetic information might be used as an adjunct to what is known about the child’s environment and their performance on standardized tests of reading. The key advantage of genetic information is that it could allow much earlier identification of children who would benefit from extra learning support,” she said.

More research is needed to understand the interaction between genes and the environment, Dr. Luciano said. “It is essential that we understand what environmental learning support can minimize genetic predisposition to dyslexia.”
 

Too soon for clinical utility

The study findings are an important foundation for additional research, but not yet clinically useful, Dr. Lessin said in an interview.

“Dyslexia is a tough diagnosis,” that requires assessment by a developmental pediatrician or a pediatric neurologist and these specialists are often not accessible to many parents, Dr. Lessin noted.

In the current study, the researchers found a number of genes potentially associated with dyslexia, but the study does not prove causality, he emphasized. The findings simply mean that some of these genes may have something to do with dyslexia, and further research might identify a genetic cause.

“No one is going to make a diagnosis of dyslexia based on genes just yet,” said Dr. Lessin. In the meantime, clinicians should be aware that good research is being conducted, and that the genetic foundations for dyslexia are being explored.

Lead author Dr. Doust and corresponding author Dr. Luciano had no financial conflicts to disclose. Several coauthors disclosed support from the Max Planck Society (Germany), the National Natural Science Foundation of China, Funds for Humanities and Social Sciences Research of the Ministry of Education, and General Project of Shaanxi Natural Science Basic Research Program. Two coauthors are employed by and hold stock or stock options in 23andMe. Dr. Lessin had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

Researchers have identified a set of 42 genes that are associated with dyslexia, based on data from approximately 50,000 dyslexic individuals and 1 million controls.

Dyslexia occurs in 5%-17% of the general population, depending on the diagnostic criteria, and has been linked with speech and language disorders, as well as ADHD, Catherine Doust, PhD, of the University of Edinburgh and colleagues wrote.

However, previous studies of the genetics of dyslexia are limited, corresponding author Michelle Luciano, PhD, said in an interview. “So much progress has been made in understanding the genetics of behavior and health, but only a small genomewide study of dyslexia existed before ours.”

Currently, genetic testing for dyslexia alone is not done.

“You couldn’t order a genetic test for dyslexia unless it were part of another genetic panel,” according to Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y.

There are also known associations with some genes and autism, but none are definitive, and testing requires a workup of which a genetic panel may be a part. Such tests are expensive, and rarely covered by insurance, the pediatrician explained. 

Experts recommend genetic screening for every child with developmental delay, but most insurance won’t cover it, Dr. Lessin continued.

In the new genomewide association study published in Nature Genetics, the researchers reviewed data from 51,800 adults aged 18 years and older with a self-reported dyslexia diagnosis and 1,087,070 controls. All study participants are enrolled in ongoing research with 23andMe, the personal genetics company.

The researchers investigated the genetic correlations with reading and related skills and evaluated evidence for genes previously associated with dyslexia. The mean ages of the dyslexia cases and controls were 49.6 years and 51.7 years, respectively.

The researchers identified 42 independent genetic variants (genomewide significant loci) associated with dyslexia; 15 of these loci were in genes previously associated with cognitive ability and educational attainment, and 27 were newly identified as specifically associated with dyslexia. The researchers further determined that 12 of the newly identified genes were associated with proficiency in reading and spelling in English and European languages, and 1 in a Chinese-language population.

A polygenic risk score is a way to characterize an individual’s risk of developing a disease, based on the total number of genetic changes related to the disease; the researchers used this score to validate their results. Dyslexia polygenic scores were used to predict reading and spelling in additional population-based and reading disorder–enriched samples outside of the study population; these genetic measures explained up to 6% of variance in reading traits, the researchers noted. Ultimately, these scores may be a tool to help identify children with a predisposition for dyslexia so reading skills support can begin early.

The researchers also found that many of the genes associated with dyslexia are also associated with ADHD, (24% of dyslexia patients reporting ADHD vs. 9% of controls), and with a moderate correlation, which suggests possible shared genetic components for deficits in working memory and attention.

The study findings were limited by the inability to prove causality, and by the potential bias in the study sample, but were strengthened by the large study population, the researchers noted.
 

Potential implications for reading and spelling

“We were surprised that none of the previous dyslexia candidate genes were genomewide significant in our study; all of our discoveries were in new genes that had not been previously implicated in dyslexia,” Dr. Luciano said in an interview. “Some of these genes have been found to be associated with general cognitive ability, but most were novel and may represent genes specifically related to cognitive processes dominant in reading and spelling.

“We were also surprised that there was little genetic correlation (or overlap) with brain MRI variables, given that brain regions have been linked to reading skill. This suggests that the link is environmental in origin,” she added.

“Our results do not directly feed into clinical practice,” said Dr. Luciano. However, “the moderate genetic overlap with ADHD suggests that broader assessments of behavior are important when a child presents with dyslexia, as co-occurrence with other conditions might influence the intervention chosen. Asking about family history of dyslexia might also help in identification.

With more research, genetic studies may find a place in the clinical setting, said Dr. Luciano.  

“As genomewide association studies become larger and the findings more stable, genetic information might be used as an adjunct to what is known about the child’s environment and their performance on standardized tests of reading. The key advantage of genetic information is that it could allow much earlier identification of children who would benefit from extra learning support,” she said.

More research is needed to understand the interaction between genes and the environment, Dr. Luciano said. “It is essential that we understand what environmental learning support can minimize genetic predisposition to dyslexia.”
 

Too soon for clinical utility

The study findings are an important foundation for additional research, but not yet clinically useful, Dr. Lessin said in an interview.

“Dyslexia is a tough diagnosis,” that requires assessment by a developmental pediatrician or a pediatric neurologist and these specialists are often not accessible to many parents, Dr. Lessin noted.

In the current study, the researchers found a number of genes potentially associated with dyslexia, but the study does not prove causality, he emphasized. The findings simply mean that some of these genes may have something to do with dyslexia, and further research might identify a genetic cause.

“No one is going to make a diagnosis of dyslexia based on genes just yet,” said Dr. Lessin. In the meantime, clinicians should be aware that good research is being conducted, and that the genetic foundations for dyslexia are being explored.

Lead author Dr. Doust and corresponding author Dr. Luciano had no financial conflicts to disclose. Several coauthors disclosed support from the Max Planck Society (Germany), the National Natural Science Foundation of China, Funds for Humanities and Social Sciences Research of the Ministry of Education, and General Project of Shaanxi Natural Science Basic Research Program. Two coauthors are employed by and hold stock or stock options in 23andMe. Dr. Lessin had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

Dementia and mild cognitive impairment (MCI) disproportionately affect Black and Hispanic individuals, as well as people with less education, based on new U.S. data from The Health and Retirement Study (HRS).

These inequities likely stem from structural racism and income inequality, necessitating a multifaceted response at an institutional level, according to lead author Jennifer J. Manly, PhD, a professor of neuropsychology in neurology at the Gertrude H. Sergievsky Center and the Taub Institute for Research in Aging and Alzheimer’s Disease at Columbia University, New York.
 

A more representative dataset

Between 2001 and 2003, a subset of HRS participants underwent extensive neuropsychological assessment in the Aging, Demographics, and Memory Study (ADAMS), providing data which have since been cited by hundreds of published studies, the investigators wrote in JAMA Neurology. Those data, however, failed to accurately represent the U.S. population at the time, and have not been updated since.

“The ADAMS substudy was small, and the limited inclusion of Black, Hispanic, and American Indian or Alaska Native participants contributed to lack of precision of estimates among minoritized racial and ethnic groups that have been shown to experience a higher burden of cognitive impairment and dementia,” Dr. Manly and colleagues wrote.

The present analysis used a more representative dataset from HRS participants who were 65 years or older in 2016. From June 2016 to October 2017, 3,496 of these individuals underwent comprehensive neuropsychological test battery and informant interview, with dementia and MCI classified based on standard diagnostic criteria.

In total, 393 people were classified with dementia (10%), while 804 had MCI (22%), both of which approximate estimates reported by previous studies, according to the investigators. In further alignment with past research, age was a clear risk factor; each 5-year increment added 17% and 95% increased risk of MCI and dementia, respectively.

Compared with college-educated participants, individuals who did not graduate from high school had a 60% increased risk for both dementia (odds ratio, 1.6; 95% confidence interval, 1.1-2.3) and MCI (OR, 1.6; 95% CI, 1.2-2.2). Other educational strata were not associated with significant differences in risk.

Compared with White participants, Black individuals had an 80% increased risk of dementia (OR, 1.8; 95% CI, 1.2-2.7), but no increased risk of MCI. Conversely, non-White Hispanic individuals had a 40% increased risk of MCI (OR, 1.4; 95% CI, 1.0-2.0), but no increased risk of dementia, compared with White participants.

“Older adults racialized as Black and Hispanic are more likely to develop cognitive impairment and dementia because of historical and current structural racism and income inequality that restrict access to brain-health benefits and increase exposure to harm,” Dr. Manly said in a written comment.

These inequities deserve a comprehensive response, she added.

“Actions and policies that decrease discriminatory and aggressive policing policies, invest in schools that serve children that are racialized as Black and Hispanic, repair housing and economic inequalities, and provide equitable access to mental and physical health, can help to narrow disparities in later life cognitive impairment,” Dr. Manly said. “Two other areas of focus for policy makers are the shortage in the workforce of dementia care specialists, and paid family leave for caregiving.”
 

Acknowledging the needs of the historically underrepresented

Lealani Mae Acosta, MD, MPH, associate professor of neurology at Vanderbilt University Medical Center, Nashville, Tenn., applauded the investigators for their “conscious effort to expand representation of historically underrepresented minorities.”

The findings themselves support what has been previously reported, Dr. Acosta said in an interview, including the disproportionate burden of cognitive disorders among people of color and those with less education.

Clinicians need to recognize that certain patient groups face increased risks of cognitive disorders, and should be screened accordingly, Dr. Acosta said, noting that all aging patients should undergo such screening. The push for screening should also occur on a community level, along with efforts to build trust between at-risk populations and health care providers.

While Dr. Acosta reiterated the importance of these new data from Black and Hispanic individuals, she noted that gaps in representation remain, and methods of characterizing populations deserve refinement.

“I’m a little bit biased because I’m an Asian physician,” Dr. Acosta said. “As much as I’m glad that they’re highlighting these different disparities, there weren’t enough [participants in] specific subgroups like American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, to be able to identify specific trends within [those groups] that are, again, historically underrepresented patient populations.”

Grouping all people of Asian descent may also be an oversimplification, she added, as differences may exist between individuals originating from different countries.

“We always have to be careful about lumping certain groups together in analyses,” Dr. Acosta said. “That’s just another reminder to us – as clinicians, as researchers – that we need to do better by our patients by expanding research opportunities, and really studying these historically underrepresented populations.”

The study was supported by the National Institute on Aging. The investigators disclosed additional relationships with the Alzheimer’s Association and the National Institutes of Health. Dr. Acosta reported no relevant competing interests.

Dementia and mild cognitive impairment (MCI) disproportionately affect Black and Hispanic individuals, as well as people with less education, based on new U.S. data from The Health and Retirement Study (HRS).

These inequities likely stem from structural racism and income inequality, necessitating a multifaceted response at an institutional level, according to lead author Jennifer J. Manly, PhD, a professor of neuropsychology in neurology at the Gertrude H. Sergievsky Center and the Taub Institute for Research in Aging and Alzheimer’s Disease at Columbia University, New York.
 

A more representative dataset

Between 2001 and 2003, a subset of HRS participants underwent extensive neuropsychological assessment in the Aging, Demographics, and Memory Study (ADAMS), providing data which have since been cited by hundreds of published studies, the investigators wrote in JAMA Neurology. Those data, however, failed to accurately represent the U.S. population at the time, and have not been updated since.

“The ADAMS substudy was small, and the limited inclusion of Black, Hispanic, and American Indian or Alaska Native participants contributed to lack of precision of estimates among minoritized racial and ethnic groups that have been shown to experience a higher burden of cognitive impairment and dementia,” Dr. Manly and colleagues wrote.

The present analysis used a more representative dataset from HRS participants who were 65 years or older in 2016. From June 2016 to October 2017, 3,496 of these individuals underwent comprehensive neuropsychological test battery and informant interview, with dementia and MCI classified based on standard diagnostic criteria.

In total, 393 people were classified with dementia (10%), while 804 had MCI (22%), both of which approximate estimates reported by previous studies, according to the investigators. In further alignment with past research, age was a clear risk factor; each 5-year increment added 17% and 95% increased risk of MCI and dementia, respectively.

Compared with college-educated participants, individuals who did not graduate from high school had a 60% increased risk for both dementia (odds ratio, 1.6; 95% confidence interval, 1.1-2.3) and MCI (OR, 1.6; 95% CI, 1.2-2.2). Other educational strata were not associated with significant differences in risk.

Compared with White participants, Black individuals had an 80% increased risk of dementia (OR, 1.8; 95% CI, 1.2-2.7), but no increased risk of MCI. Conversely, non-White Hispanic individuals had a 40% increased risk of MCI (OR, 1.4; 95% CI, 1.0-2.0), but no increased risk of dementia, compared with White participants.

“Older adults racialized as Black and Hispanic are more likely to develop cognitive impairment and dementia because of historical and current structural racism and income inequality that restrict access to brain-health benefits and increase exposure to harm,” Dr. Manly said in a written comment.

These inequities deserve a comprehensive response, she added.

“Actions and policies that decrease discriminatory and aggressive policing policies, invest in schools that serve children that are racialized as Black and Hispanic, repair housing and economic inequalities, and provide equitable access to mental and physical health, can help to narrow disparities in later life cognitive impairment,” Dr. Manly said. “Two other areas of focus for policy makers are the shortage in the workforce of dementia care specialists, and paid family leave for caregiving.”
 

Acknowledging the needs of the historically underrepresented

Lealani Mae Acosta, MD, MPH, associate professor of neurology at Vanderbilt University Medical Center, Nashville, Tenn., applauded the investigators for their “conscious effort to expand representation of historically underrepresented minorities.”

The findings themselves support what has been previously reported, Dr. Acosta said in an interview, including the disproportionate burden of cognitive disorders among people of color and those with less education.

Clinicians need to recognize that certain patient groups face increased risks of cognitive disorders, and should be screened accordingly, Dr. Acosta said, noting that all aging patients should undergo such screening. The push for screening should also occur on a community level, along with efforts to build trust between at-risk populations and health care providers.

While Dr. Acosta reiterated the importance of these new data from Black and Hispanic individuals, she noted that gaps in representation remain, and methods of characterizing populations deserve refinement.

“I’m a little bit biased because I’m an Asian physician,” Dr. Acosta said. “As much as I’m glad that they’re highlighting these different disparities, there weren’t enough [participants in] specific subgroups like American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, to be able to identify specific trends within [those groups] that are, again, historically underrepresented patient populations.”

Grouping all people of Asian descent may also be an oversimplification, she added, as differences may exist between individuals originating from different countries.

“We always have to be careful about lumping certain groups together in analyses,” Dr. Acosta said. “That’s just another reminder to us – as clinicians, as researchers – that we need to do better by our patients by expanding research opportunities, and really studying these historically underrepresented populations.”

The study was supported by the National Institute on Aging. The investigators disclosed additional relationships with the Alzheimer’s Association and the National Institutes of Health. Dr. Acosta reported no relevant competing interests.

Dementia and mild cognitive impairment (MCI) disproportionately affect Black and Hispanic individuals, as well as people with less education, based on new U.S. data from The Health and Retirement Study (HRS).

These inequities likely stem from structural racism and income inequality, necessitating a multifaceted response at an institutional level, according to lead author Jennifer J. Manly, PhD, a professor of neuropsychology in neurology at the Gertrude H. Sergievsky Center and the Taub Institute for Research in Aging and Alzheimer’s Disease at Columbia University, New York.
 

A more representative dataset

Between 2001 and 2003, a subset of HRS participants underwent extensive neuropsychological assessment in the Aging, Demographics, and Memory Study (ADAMS), providing data which have since been cited by hundreds of published studies, the investigators wrote in JAMA Neurology. Those data, however, failed to accurately represent the U.S. population at the time, and have not been updated since.

“The ADAMS substudy was small, and the limited inclusion of Black, Hispanic, and American Indian or Alaska Native participants contributed to lack of precision of estimates among minoritized racial and ethnic groups that have been shown to experience a higher burden of cognitive impairment and dementia,” Dr. Manly and colleagues wrote.

The present analysis used a more representative dataset from HRS participants who were 65 years or older in 2016. From June 2016 to October 2017, 3,496 of these individuals underwent comprehensive neuropsychological test battery and informant interview, with dementia and MCI classified based on standard diagnostic criteria.

In total, 393 people were classified with dementia (10%), while 804 had MCI (22%), both of which approximate estimates reported by previous studies, according to the investigators. In further alignment with past research, age was a clear risk factor; each 5-year increment added 17% and 95% increased risk of MCI and dementia, respectively.

Compared with college-educated participants, individuals who did not graduate from high school had a 60% increased risk for both dementia (odds ratio, 1.6; 95% confidence interval, 1.1-2.3) and MCI (OR, 1.6; 95% CI, 1.2-2.2). Other educational strata were not associated with significant differences in risk.

Compared with White participants, Black individuals had an 80% increased risk of dementia (OR, 1.8; 95% CI, 1.2-2.7), but no increased risk of MCI. Conversely, non-White Hispanic individuals had a 40% increased risk of MCI (OR, 1.4; 95% CI, 1.0-2.0), but no increased risk of dementia, compared with White participants.

“Older adults racialized as Black and Hispanic are more likely to develop cognitive impairment and dementia because of historical and current structural racism and income inequality that restrict access to brain-health benefits and increase exposure to harm,” Dr. Manly said in a written comment.

These inequities deserve a comprehensive response, she added.

“Actions and policies that decrease discriminatory and aggressive policing policies, invest in schools that serve children that are racialized as Black and Hispanic, repair housing and economic inequalities, and provide equitable access to mental and physical health, can help to narrow disparities in later life cognitive impairment,” Dr. Manly said. “Two other areas of focus for policy makers are the shortage in the workforce of dementia care specialists, and paid family leave for caregiving.”
 

Acknowledging the needs of the historically underrepresented

Lealani Mae Acosta, MD, MPH, associate professor of neurology at Vanderbilt University Medical Center, Nashville, Tenn., applauded the investigators for their “conscious effort to expand representation of historically underrepresented minorities.”

The findings themselves support what has been previously reported, Dr. Acosta said in an interview, including the disproportionate burden of cognitive disorders among people of color and those with less education.

Clinicians need to recognize that certain patient groups face increased risks of cognitive disorders, and should be screened accordingly, Dr. Acosta said, noting that all aging patients should undergo such screening. The push for screening should also occur on a community level, along with efforts to build trust between at-risk populations and health care providers.

While Dr. Acosta reiterated the importance of these new data from Black and Hispanic individuals, she noted that gaps in representation remain, and methods of characterizing populations deserve refinement.

“I’m a little bit biased because I’m an Asian physician,” Dr. Acosta said. “As much as I’m glad that they’re highlighting these different disparities, there weren’t enough [participants in] specific subgroups like American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, to be able to identify specific trends within [those groups] that are, again, historically underrepresented patient populations.”

Grouping all people of Asian descent may also be an oversimplification, she added, as differences may exist between individuals originating from different countries.

“We always have to be careful about lumping certain groups together in analyses,” Dr. Acosta said. “That’s just another reminder to us – as clinicians, as researchers – that we need to do better by our patients by expanding research opportunities, and really studying these historically underrepresented populations.”

The study was supported by the National Institute on Aging. The investigators disclosed additional relationships with the Alzheimer’s Association and the National Institutes of Health. Dr. Acosta reported no relevant competing interests.

Renal function should be considered when determining whether to pick ticagrelor-aspirin or clopidogrel-aspirin as the antiplatelet therapy for patients with minor stroke, according to new research.

The study, which was conducted in 202 centers in China and published in Annals of Internal Medicine, indicates that when patients had normal kidney function, ticagrelor-aspirin, compared with clopidogrel-aspirin, substantially reduced the risk for recurrent stroke within 90 days of follow-up.

However, this effect was not seen in patients with mildly, moderately or severely decreased kidney function.

Rates of severe or moderate bleeding did not differ substantially between the two treatments.
 

Results gleaned from CHANCE-2 data

The researchers, led by Anxin Wang, PhD, from Capital Medical University in Beijing, conducted a post hoc analysis of the CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) trial.

The trial included 6,378 patients who carried cytochrome P450 2C19 (CYP2C19) loss-of-function (LOF) alleles who had experienced a minor stroke or transient ischemic attack.

Patients received either ticagrelor-aspirin or clopidogrel-aspirin, and their renal function was measured by estimated glomerular filtration rate. The authors listed as a limitation that no data were available on the presence of albuminuria or proteinuria.

The researchers investigated what effect renal function had on the efficacy and safety of the therapies.
 

Differences in the therapies

Clopidogrel-aspirin is often recommended for preventing stroke. It can reduce thrombotic risk in patients with impaired kidney function, the authors noted. Ticagrelor can provide greater, faster, and more consistent P2Y12 inhibition than clopidogrel, and evidence shows it is effective in preventing stroke recurrence, particularly in people carrying CYP2C19 LOF alleles.

When people have reduced kidney function, clopidogrel may be harder to clear than ticagrelor and there may be increased plasma concentrations, so function is important to consider when choosing an antiplatelet therapy, the authors wrote.
 

Choice may come down to cost

Geoffrey Barnes, MD, MSc, associate professor of vascular and cardiovascular medicine at University of Michigan Medicine in Ann Arbor, said in an interview that there has been momentum toward ticagrelor as a more potent choice than clopidogrel not just in populations with minor stroke but for people with MI and coronary stents.

He said he found the results surprising and was intrigued that this paper suggests looking more skeptically at ticagrelor when kidney function is impaired.

Still, the choice may also come down to what the patient can afford at the pharmacy, he said.

“The reality is many patients still get clopidogrel either because that’s what their physicians have been prescribing for well over a decade or because of cost issues, and clopidogrel, for many patients, can be less expensive,” Dr. Barnes noted.

He said he would like to see more study in different populations as the prevalence of people carrying CYP2C19 allele differs by race and results might be different in a non-Asian population. That allele is thought to affect how clopidogrel is metabolized.
 

Study should spur more research

Nada El Husseini, MD, associate professor of neurology and Duke Telestroke Medical Director at Duke University Medical Center, Durham, N.C., said the study is hypothesis generating, but shouldn’t be thought of as the last word on the subject.

She pointed out some additional limitations of the study, including that it was a post hoc analysis. She explained that the question researchers asked in this study – about effect of kidney function on the safety and efficacy of the therapies – was not the focus of the original CHANCE-2 study, and, as such, the post hoc study may have been underpowered to answer the renal function question.

The authors acknowledged that limitation, noting that “the proportion of patients with severely decreased renal function was low.”

Among 6,378 patients, 4,050 (63.5%) had normal kidney function, 2,010 (31.5%) had mildly decreased function, and 318 (5.0%) had moderately to severely decreased function.

The study was funded by the Ministry of Science and Technology of the People’s Republic of China, the Beijing Municipal Science and Technology Commission, the Chinese Stroke Association, the National Science and Technology Major Project and the Beijing Municipal Administration of Hospitals Incubating Program). Salubris Pharmaceuticals contributed ticagrelor and, clopidogrel at no cost and with no restrictions. Dr. Wang reported no relevant financial relationships. Dr. Barnes and Dr. El Husseini reported no relevant financial relationships.

Renal function should be considered when determining whether to pick ticagrelor-aspirin or clopidogrel-aspirin as the antiplatelet therapy for patients with minor stroke, according to new research.

The study, which was conducted in 202 centers in China and published in Annals of Internal Medicine, indicates that when patients had normal kidney function, ticagrelor-aspirin, compared with clopidogrel-aspirin, substantially reduced the risk for recurrent stroke within 90 days of follow-up.

However, this effect was not seen in patients with mildly, moderately or severely decreased kidney function.

Rates of severe or moderate bleeding did not differ substantially between the two treatments.
 

Results gleaned from CHANCE-2 data

The researchers, led by Anxin Wang, PhD, from Capital Medical University in Beijing, conducted a post hoc analysis of the CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) trial.

The trial included 6,378 patients who carried cytochrome P450 2C19 (CYP2C19) loss-of-function (LOF) alleles who had experienced a minor stroke or transient ischemic attack.

Patients received either ticagrelor-aspirin or clopidogrel-aspirin, and their renal function was measured by estimated glomerular filtration rate. The authors listed as a limitation that no data were available on the presence of albuminuria or proteinuria.

The researchers investigated what effect renal function had on the efficacy and safety of the therapies.
 

Differences in the therapies

Clopidogrel-aspirin is often recommended for preventing stroke. It can reduce thrombotic risk in patients with impaired kidney function, the authors noted. Ticagrelor can provide greater, faster, and more consistent P2Y12 inhibition than clopidogrel, and evidence shows it is effective in preventing stroke recurrence, particularly in people carrying CYP2C19 LOF alleles.

When people have reduced kidney function, clopidogrel may be harder to clear than ticagrelor and there may be increased plasma concentrations, so function is important to consider when choosing an antiplatelet therapy, the authors wrote.
 

Choice may come down to cost

Geoffrey Barnes, MD, MSc, associate professor of vascular and cardiovascular medicine at University of Michigan Medicine in Ann Arbor, said in an interview that there has been momentum toward ticagrelor as a more potent choice than clopidogrel not just in populations with minor stroke but for people with MI and coronary stents.

He said he found the results surprising and was intrigued that this paper suggests looking more skeptically at ticagrelor when kidney function is impaired.

Still, the choice may also come down to what the patient can afford at the pharmacy, he said.

“The reality is many patients still get clopidogrel either because that’s what their physicians have been prescribing for well over a decade or because of cost issues, and clopidogrel, for many patients, can be less expensive,” Dr. Barnes noted.

He said he would like to see more study in different populations as the prevalence of people carrying CYP2C19 allele differs by race and results might be different in a non-Asian population. That allele is thought to affect how clopidogrel is metabolized.
 

Study should spur more research

Nada El Husseini, MD, associate professor of neurology and Duke Telestroke Medical Director at Duke University Medical Center, Durham, N.C., said the study is hypothesis generating, but shouldn’t be thought of as the last word on the subject.

She pointed out some additional limitations of the study, including that it was a post hoc analysis. She explained that the question researchers asked in this study – about effect of kidney function on the safety and efficacy of the therapies – was not the focus of the original CHANCE-2 study, and, as such, the post hoc study may have been underpowered to answer the renal function question.

The authors acknowledged that limitation, noting that “the proportion of patients with severely decreased renal function was low.”

Among 6,378 patients, 4,050 (63.5%) had normal kidney function, 2,010 (31.5%) had mildly decreased function, and 318 (5.0%) had moderately to severely decreased function.

The study was funded by the Ministry of Science and Technology of the People’s Republic of China, the Beijing Municipal Science and Technology Commission, the Chinese Stroke Association, the National Science and Technology Major Project and the Beijing Municipal Administration of Hospitals Incubating Program). Salubris Pharmaceuticals contributed ticagrelor and, clopidogrel at no cost and with no restrictions. Dr. Wang reported no relevant financial relationships. Dr. Barnes and Dr. El Husseini reported no relevant financial relationships.

Renal function should be considered when determining whether to pick ticagrelor-aspirin or clopidogrel-aspirin as the antiplatelet therapy for patients with minor stroke, according to new research.

The study, which was conducted in 202 centers in China and published in Annals of Internal Medicine, indicates that when patients had normal kidney function, ticagrelor-aspirin, compared with clopidogrel-aspirin, substantially reduced the risk for recurrent stroke within 90 days of follow-up.

However, this effect was not seen in patients with mildly, moderately or severely decreased kidney function.

Rates of severe or moderate bleeding did not differ substantially between the two treatments.
 

Results gleaned from CHANCE-2 data

The researchers, led by Anxin Wang, PhD, from Capital Medical University in Beijing, conducted a post hoc analysis of the CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) trial.

The trial included 6,378 patients who carried cytochrome P450 2C19 (CYP2C19) loss-of-function (LOF) alleles who had experienced a minor stroke or transient ischemic attack.

Patients received either ticagrelor-aspirin or clopidogrel-aspirin, and their renal function was measured by estimated glomerular filtration rate. The authors listed as a limitation that no data were available on the presence of albuminuria or proteinuria.

The researchers investigated what effect renal function had on the efficacy and safety of the therapies.
 

Differences in the therapies

Clopidogrel-aspirin is often recommended for preventing stroke. It can reduce thrombotic risk in patients with impaired kidney function, the authors noted. Ticagrelor can provide greater, faster, and more consistent P2Y12 inhibition than clopidogrel, and evidence shows it is effective in preventing stroke recurrence, particularly in people carrying CYP2C19 LOF alleles.

When people have reduced kidney function, clopidogrel may be harder to clear than ticagrelor and there may be increased plasma concentrations, so function is important to consider when choosing an antiplatelet therapy, the authors wrote.
 

Choice may come down to cost

Geoffrey Barnes, MD, MSc, associate professor of vascular and cardiovascular medicine at University of Michigan Medicine in Ann Arbor, said in an interview that there has been momentum toward ticagrelor as a more potent choice than clopidogrel not just in populations with minor stroke but for people with MI and coronary stents.

He said he found the results surprising and was intrigued that this paper suggests looking more skeptically at ticagrelor when kidney function is impaired.

Still, the choice may also come down to what the patient can afford at the pharmacy, he said.

“The reality is many patients still get clopidogrel either because that’s what their physicians have been prescribing for well over a decade or because of cost issues, and clopidogrel, for many patients, can be less expensive,” Dr. Barnes noted.

He said he would like to see more study in different populations as the prevalence of people carrying CYP2C19 allele differs by race and results might be different in a non-Asian population. That allele is thought to affect how clopidogrel is metabolized.
 

Study should spur more research

Nada El Husseini, MD, associate professor of neurology and Duke Telestroke Medical Director at Duke University Medical Center, Durham, N.C., said the study is hypothesis generating, but shouldn’t be thought of as the last word on the subject.

She pointed out some additional limitations of the study, including that it was a post hoc analysis. She explained that the question researchers asked in this study – about effect of kidney function on the safety and efficacy of the therapies – was not the focus of the original CHANCE-2 study, and, as such, the post hoc study may have been underpowered to answer the renal function question.

The authors acknowledged that limitation, noting that “the proportion of patients with severely decreased renal function was low.”

Among 6,378 patients, 4,050 (63.5%) had normal kidney function, 2,010 (31.5%) had mildly decreased function, and 318 (5.0%) had moderately to severely decreased function.

The study was funded by the Ministry of Science and Technology of the People’s Republic of China, the Beijing Municipal Science and Technology Commission, the Chinese Stroke Association, the National Science and Technology Major Project and the Beijing Municipal Administration of Hospitals Incubating Program). Salubris Pharmaceuticals contributed ticagrelor and, clopidogrel at no cost and with no restrictions. Dr. Wang reported no relevant financial relationships. Dr. Barnes and Dr. El Husseini reported no relevant financial relationships.