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BP control slowed brain damage in elderly hypertensives
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
This is another dataset showing that blood pressure reduction in elderly people with hypertension is safe and extremely important. Clinicians today often exclude elderly patients from aggressive blood pressure control because of an unrealized fear of causing hypotension and falls. These new data add to what’s already been reported in support of the American College of Cardiology and American Heart Association blood pressure treatment target of less than 130/80 mm Hg for noninstitutionalized, ambulatory, community-dwelling adults who are aged at least 65 years (Hypertension. 2018 June;71[6]:e13-e115). Many clinicians continue to have concerns about what this guideline says about treating older patients. These new findings support the idea that blood pressure can safely be treated to the level the guideline recommends while producing signals of beneficial changes in brain health and in cognitive function.
Providers worry a lot about the potential for harm from treatment. These findings add to the data that say clinicians can safely follow the blood pressure management guideline to benefit even very old patients.
Eileen Handberg, PhD , is a research professor of medicine and director of the Cardiovascular Clinical Trials Program at the University of Florida in Gainesville. She had no relevant disclosures. She made these comments in an interview.
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
NEW ORLEANS – Hypertensive elderly patients treated to maintain an ambulatory systolic blood pressure of 130 mm Hg had significantly slower progression of white matter lesions in their brains than did control hypertensive patients maintained at an ambulatory systolic pressure of about 145 mm Hg during 3 years of follow-up in a randomized, single-center study with 199 patients.
The results also showed similar rates of death, syncope episodes, and falls in the intensively and less rigorously treated subgroups, and the patients treated to a systolic of 130 mm Hg also had significantly fewer nonfatal cardiovascular disease events, further documenting the safety and efficacy in elderly patients of a more aggressive blood pressure goal like the one promoted in current guidelines from the American College of Cardiology and American Heart Association, William B. White, MD, said at the annual meeting of the American College of Cardiology.
The study’s findings also showed that in one measure of cognitive function, the serial reaction time task, the patients treated to a systolic pressure of 130 mm Hg had an average 23 millisecond improvement in their reaction time from baseline to their 3-year follow-up, while patients in the control group treated to a systolic pressure of 145 mm Hg had a 33 millisecond increase in their average reaction time during follow-up. This 56 millisecond between-group difference from baseline in average change in reaction time over 3 years was both statistically significant and represents a clinically meaningful difference for a measure of both processing speed and executive function, said Dr. White, professor of medicine at the University of Connecticut in Farmington. However, the participants also underwent assessment by five other clinical measures of cognitive function and in none of the other five tests did more intensive blood pressure control link with an improvement, compared with the results in control patients.
The study had two primary endpoints. One was progression of white matter hyperintensity on brain MR images, which is a measure of neuron necrosis in the brain, and this analysis showed that the growth of white matter occurred at a 40% reduced rate among 99 patients treated to an average ambulatory systolic blood pressure of 130 mm Hg, compared with the average progression among 100 controls treated to an average ambulatory systolic of 145 mm Hg. The second measure was improvement during 3 years, compared with controls, in any of six different measures of mobility, including gait speed. The results showed no significant differences between the treatment arms in any of these measures. The average progression of white matter disease among control patients after 3 years was of a magnitude that would trigger concern in a neurologist who saw these scans, said Dr. White. The researchers could already begin to see a between-group difference in the accumulation of white matter hyperintensity on the MR scans of patients at 18 months in the study, he added.
During his presentation, Dr. White suggested that the absence of discerned improvements in mobility from more aggressive blood pressure control despite the observed slowed progression of white matter disease may have resulted from the study’s relatively brief follow-up.
The INFINITY (Intensive versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the Elderly) study enrolled hypertensive patients at least 75 years old who already showed visible evidence of white matter hypertrophy on their brain MR scan at baseline but also had normal mobility and mental function (their baseline score on the mini mental state examination had to be within the normal range, with an average score of 28 among enrolled patients), and they had no history of any chronic neurological condition (Am Heart J. 2013 Mar;165[3]:258-65). The median age of enrolled patients was 80 years. They had an average of 15 years of education, indicating a study cohort with a high level of education and function, Dr. White noted. The inclusion and exclusion criteria led to a study population that was substantially older but without as much comorbidity as patients enrolled in the SPRINT MIND study (JAMA. 2019 Jan 28;321[6]:553-61), he said. The study exclusively used 24-hour ambulatory monitoring for baseline and follow-up blood pressure measurements.
The participating clinicians successfully maintained patients in each of the treatment groups at close to their goal systolic blood pressures. At 18 months, the actual average systolic pressures among patients in the two study groups were 132 mm Hg and 146 mm Hg, and at 36 months their pressures averaged 131 mm Hg and 146 mm Hg for 163 patients who remained in the study out to 36-months. Maintenance of the lower pressure generally required treatment with one additional antihypertensive medication, compared with the control patients’ treatment, Dr. White said.
The rates of total falls and falls causing injury were virtually identical in the two treatment groups. The incidence of nonfatal cardiovascular disease events over 3 years, including MI, strokes, and cardiovascular disease hospitalizations, was 4 cases in the intensively-treated patients and 17 among those treated to a higher systolic pressure, a statistically significant and unexpected difference, Dr. White reported.
REPORTING FROM ACC 19
Biogen, Eisai discontinue aducanumab Alzheimer’s trials
Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.
The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.
In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.
Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.
“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.
Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.
The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.
In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.
Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.
“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.
Biogen and Eisai have announced that they are discontinuing the ENGAGE and EMERGE trials, which were designed to test the efficacy and safety of aducanumab in patients with mild cognitive impairment caused by Alzheimer’s disease and mild Alzheimer’s disease dementia.
The phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials were canceled not because of safety concerns but because of a futility analysis conducted by an independent data monitoring committee that indicated the drug would not meet the trials’ primary endpoint, which was the slowing of cognitive and functional impairment as measured by changes in Clinical Dementia Rating–Sum of Boxes score, compared with placebo.
In addition to ENGAGE and EMERGE, the phase 2 EVOLVE safety study and the long-term extension of the phase 1b PRIME study have also been canceled. Data from the ENGAGE and EMERGE trials will be presented at future medical meetings.
Aducanumab is a human monoclonal antibody derived from B cells collected from healthy elderly subjects with no cognitive decline or those with unusually slow cognitive decline through Neurimmune’s technology platform called Reverse Translational Medicine. It was granted Fast Track designation by the Food and Drug Administration.
“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience. We are incredibly grateful to all the Alzheimer’s disease patients, their families, and the investigators who participated in the trials and contributed greatly to this research,” Michel Vounatsos, CEO at Biogen, said in a press release.
Alzheimer’s update: George Grossberg
Dr. Grossberg is the Samuel W. Fordyce professor and director of geriatric psychiatry at Saint Louis University.
And later, Dr. RK talks MDQ.
You can find more from Dr. Grossberg, including videos and articles, by clicking here.
Amazon
Apple Podcasts
Google Podcasts
Spotify
Dr. Grossberg is the Samuel W. Fordyce professor and director of geriatric psychiatry at Saint Louis University.
And later, Dr. RK talks MDQ.
You can find more from Dr. Grossberg, including videos and articles, by clicking here.
Amazon
Apple Podcasts
Google Podcasts
Spotify
Dr. Grossberg is the Samuel W. Fordyce professor and director of geriatric psychiatry at Saint Louis University.
And later, Dr. RK talks MDQ.
You can find more from Dr. Grossberg, including videos and articles, by clicking here.
Amazon
Apple Podcasts
Google Podcasts
Spotify
Boosting Alzheimer’s trial participation via Medicare Advantage ‘memory fitness programs’
Clinical trials represent future hope for patients seeking better care, and there is no disease more in need of better care than Alzheimer’s disease. While death rates among most cancers, as well as heart disease, HIV-related illness, and other categories, have declined in the past decade, there has been no progress for Alzheimer’s disease. Better health and wellness overall may be having a beneficial effect that has produced a reduction in age-adjusted dementia rates, but with the aging of the population there are a greater absolute number of dementia cases than ever before, and that number is expected to continue rising. Finding a disease-modifying therapy seems to be the best hope for changing this dim outlook. Clinical trials intend to do just that but are hampered by patient enrollment rates that remain low. Far fewer eligible patients enroll than are needed, causing studies to take longer to complete, driving up their costs and essentially slowing progress. There is a need to increase patient enrollment, and there has been a variety of efforts intended to address this, not the least of which has been an explosion of media coverage of Alzheimer’s disease.
The Global Alzheimer’s Platform (GAP) Foundation, a nonprofit, self-described patient-centric entity dedicated to reducing the time and cost of Alzheimer’s disease clinical trials, recently announced an initiative to increase participation in Alzheimer’s clinical trials by supporting and collaborating with “memory fitness programs” through select Medicare Advantage plans. At worst, this seems a harmless way to increase attention and hopefully interest in clinical trial participation. At best, this may be a cost-effective way to increase enrollment and even improve dementia care. Dementia is notoriously underdiagnosed, especially by overworked, busy primary care providers who simply lack the time to perform the time-consuming testing that is typically required to diagnose and follow such patients.
There are some caveats to consider. First, memory fitness programs are of dubious benefit. They generally fit the description of being harmless, but there is little compelling evidence that they preserve or improve memory.
Second, enrollment in a clinical trial, for a patient, is not always a winning proposition. To date, there has been little success and in the absence of benefit, any downside – even if simply an inconvenience – is a net negative. Recently at the 2018 Clinical Trials on Alzheimer’s Disease meeting, Merck reported that patients with mild cognitive impairment receiving active treatment in the BACE1 inhibitor verubecestat trial actually declined at a more rapid rate than did those on placebo. While the absolute difference was small, and one could argue whether it was clinically significant or simply a random occurrence, it was a reminder that intervention with an experimental agent is not necessarily benign.
Third, Medicare Advantage plans, while popular in some circles, are not considered advantageous to providers so that the proliferation of inadequate reimbursement will potentially fuel the accelerating number of providers who opt out of insurance plans altogether. This is not necessarily an issue for the GAP Foundation specifically but is nonetheless an issue for anything that promotes MA plans).
Finally, it remains important to help patients and families maintain a positive outlook, especially when we have nothing better to offer. Alzheimer’s disease is not a death sentence for every patient affected. While many have difficult and heartbreaking courses, some have slowly progressive courses with relatively little impairment for an extended period of time. There are also the dementia-phobic, cognitively unimpaired individuals (or who simply have normal age-associated cognitive changes) in whom the continued drumbeat of dementia awareness and memory testing raises their paranoia ever higher. We treat deficits (or try to), but we have to live based on our preserved skills. The challenge clinicians must face with patients and families is how to maximize function while compensating for deficits and making sure that patients and families maintain their hope.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Clinical trials represent future hope for patients seeking better care, and there is no disease more in need of better care than Alzheimer’s disease. While death rates among most cancers, as well as heart disease, HIV-related illness, and other categories, have declined in the past decade, there has been no progress for Alzheimer’s disease. Better health and wellness overall may be having a beneficial effect that has produced a reduction in age-adjusted dementia rates, but with the aging of the population there are a greater absolute number of dementia cases than ever before, and that number is expected to continue rising. Finding a disease-modifying therapy seems to be the best hope for changing this dim outlook. Clinical trials intend to do just that but are hampered by patient enrollment rates that remain low. Far fewer eligible patients enroll than are needed, causing studies to take longer to complete, driving up their costs and essentially slowing progress. There is a need to increase patient enrollment, and there has been a variety of efforts intended to address this, not the least of which has been an explosion of media coverage of Alzheimer’s disease.
The Global Alzheimer’s Platform (GAP) Foundation, a nonprofit, self-described patient-centric entity dedicated to reducing the time and cost of Alzheimer’s disease clinical trials, recently announced an initiative to increase participation in Alzheimer’s clinical trials by supporting and collaborating with “memory fitness programs” through select Medicare Advantage plans. At worst, this seems a harmless way to increase attention and hopefully interest in clinical trial participation. At best, this may be a cost-effective way to increase enrollment and even improve dementia care. Dementia is notoriously underdiagnosed, especially by overworked, busy primary care providers who simply lack the time to perform the time-consuming testing that is typically required to diagnose and follow such patients.
There are some caveats to consider. First, memory fitness programs are of dubious benefit. They generally fit the description of being harmless, but there is little compelling evidence that they preserve or improve memory.
Second, enrollment in a clinical trial, for a patient, is not always a winning proposition. To date, there has been little success and in the absence of benefit, any downside – even if simply an inconvenience – is a net negative. Recently at the 2018 Clinical Trials on Alzheimer’s Disease meeting, Merck reported that patients with mild cognitive impairment receiving active treatment in the BACE1 inhibitor verubecestat trial actually declined at a more rapid rate than did those on placebo. While the absolute difference was small, and one could argue whether it was clinically significant or simply a random occurrence, it was a reminder that intervention with an experimental agent is not necessarily benign.
Third, Medicare Advantage plans, while popular in some circles, are not considered advantageous to providers so that the proliferation of inadequate reimbursement will potentially fuel the accelerating number of providers who opt out of insurance plans altogether. This is not necessarily an issue for the GAP Foundation specifically but is nonetheless an issue for anything that promotes MA plans).
Finally, it remains important to help patients and families maintain a positive outlook, especially when we have nothing better to offer. Alzheimer’s disease is not a death sentence for every patient affected. While many have difficult and heartbreaking courses, some have slowly progressive courses with relatively little impairment for an extended period of time. There are also the dementia-phobic, cognitively unimpaired individuals (or who simply have normal age-associated cognitive changes) in whom the continued drumbeat of dementia awareness and memory testing raises their paranoia ever higher. We treat deficits (or try to), but we have to live based on our preserved skills. The challenge clinicians must face with patients and families is how to maximize function while compensating for deficits and making sure that patients and families maintain their hope.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Clinical trials represent future hope for patients seeking better care, and there is no disease more in need of better care than Alzheimer’s disease. While death rates among most cancers, as well as heart disease, HIV-related illness, and other categories, have declined in the past decade, there has been no progress for Alzheimer’s disease. Better health and wellness overall may be having a beneficial effect that has produced a reduction in age-adjusted dementia rates, but with the aging of the population there are a greater absolute number of dementia cases than ever before, and that number is expected to continue rising. Finding a disease-modifying therapy seems to be the best hope for changing this dim outlook. Clinical trials intend to do just that but are hampered by patient enrollment rates that remain low. Far fewer eligible patients enroll than are needed, causing studies to take longer to complete, driving up their costs and essentially slowing progress. There is a need to increase patient enrollment, and there has been a variety of efforts intended to address this, not the least of which has been an explosion of media coverage of Alzheimer’s disease.
The Global Alzheimer’s Platform (GAP) Foundation, a nonprofit, self-described patient-centric entity dedicated to reducing the time and cost of Alzheimer’s disease clinical trials, recently announced an initiative to increase participation in Alzheimer’s clinical trials by supporting and collaborating with “memory fitness programs” through select Medicare Advantage plans. At worst, this seems a harmless way to increase attention and hopefully interest in clinical trial participation. At best, this may be a cost-effective way to increase enrollment and even improve dementia care. Dementia is notoriously underdiagnosed, especially by overworked, busy primary care providers who simply lack the time to perform the time-consuming testing that is typically required to diagnose and follow such patients.
There are some caveats to consider. First, memory fitness programs are of dubious benefit. They generally fit the description of being harmless, but there is little compelling evidence that they preserve or improve memory.
Second, enrollment in a clinical trial, for a patient, is not always a winning proposition. To date, there has been little success and in the absence of benefit, any downside – even if simply an inconvenience – is a net negative. Recently at the 2018 Clinical Trials on Alzheimer’s Disease meeting, Merck reported that patients with mild cognitive impairment receiving active treatment in the BACE1 inhibitor verubecestat trial actually declined at a more rapid rate than did those on placebo. While the absolute difference was small, and one could argue whether it was clinically significant or simply a random occurrence, it was a reminder that intervention with an experimental agent is not necessarily benign.
Third, Medicare Advantage plans, while popular in some circles, are not considered advantageous to providers so that the proliferation of inadequate reimbursement will potentially fuel the accelerating number of providers who opt out of insurance plans altogether. This is not necessarily an issue for the GAP Foundation specifically but is nonetheless an issue for anything that promotes MA plans).
Finally, it remains important to help patients and families maintain a positive outlook, especially when we have nothing better to offer. Alzheimer’s disease is not a death sentence for every patient affected. While many have difficult and heartbreaking courses, some have slowly progressive courses with relatively little impairment for an extended period of time. There are also the dementia-phobic, cognitively unimpaired individuals (or who simply have normal age-associated cognitive changes) in whom the continued drumbeat of dementia awareness and memory testing raises their paranoia ever higher. We treat deficits (or try to), but we have to live based on our preserved skills. The challenge clinicians must face with patients and families is how to maximize function while compensating for deficits and making sure that patients and families maintain their hope.
Dr. Caselli is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Blood-based signature helps predict status of early AD indicator
A recently developed blood-based signature can help predict the status of an early Alzheimer’s disease risk indicator with high accuracy, investigators are reporting.
By analyzing as few as four proteins, the machine learning-derived test can predict the status of cerebrospinal fluid (CSF) amyloid beta1-42 (Abeta1-42), according to Noel G. Faux, PHD, of IBM Australia and the University of Melbourne, and co-investigators.
While shifts in Abeta1-42 may signal the presence of disease long before significant cognitive decline is clinically apparent, collection of CSF is highly invasive and expensive, Faux and investigators said in their report.
By contrast, blood biomarkers could prove to be a useful alternative not only to invasive lumbar punctures, they said, but also to the positron emission tomography (PET) evaluation of Abeta1-42, which is expensive and limited in some regions.
“In conjunction with biomarkers for neocortical amyloid burden, the CSF Abeta1-42biomarkers presented in this work may help yield a cheap, non-invasive tool for both improving clinical trials targeting amyloid and population screening,” Dr. Faux and co-authors said in Scientific Reports.
Dr. Faux and colleagues used a Random Forest approach to build models for CSF Abeta1-42 using blood biomarkers and other variables.
They found that a model incorporating age, APOEe4 carrier status, and a number of plasma protein levels predicted Abeta1-42 normal/abnormalstatus with an AUC, sensitivity and specificity of 0.84, 0.78 and 0.73 respectively.
In a model they said was more suitable for clinical application, they narrowed down the variables to 4 plasma analytes and APOEe4 carrier status, which had an AUC, sensitivity, and specificity of 0.81, 0.81 and 0.64 respectively.
They validated the models on a cohort of individuals in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a large, longitudinal, multicenter study.
Patients with mild cognitive impairment with predicted abnormal CSF Abeta1-42 levels indeed did transition to a diagnosis of Alzheimer’s disease more quickly than those with predicted normal levels, according to investigators.
That helps provide “strong evidence” that the blood-based model is generalizable, robust, and could help stratify patients based on risk of progressing to Alzheimer’s disease, they said in their report.
Dr. Faux and colleagues declared no conflicts of interest related to the research.
SOURCE: Goudey B, et al. Sci Rep. 2019 Mar 10. doi: 10.1101/190207v3.
A recently developed blood-based signature can help predict the status of an early Alzheimer’s disease risk indicator with high accuracy, investigators are reporting.
By analyzing as few as four proteins, the machine learning-derived test can predict the status of cerebrospinal fluid (CSF) amyloid beta1-42 (Abeta1-42), according to Noel G. Faux, PHD, of IBM Australia and the University of Melbourne, and co-investigators.
While shifts in Abeta1-42 may signal the presence of disease long before significant cognitive decline is clinically apparent, collection of CSF is highly invasive and expensive, Faux and investigators said in their report.
By contrast, blood biomarkers could prove to be a useful alternative not only to invasive lumbar punctures, they said, but also to the positron emission tomography (PET) evaluation of Abeta1-42, which is expensive and limited in some regions.
“In conjunction with biomarkers for neocortical amyloid burden, the CSF Abeta1-42biomarkers presented in this work may help yield a cheap, non-invasive tool for both improving clinical trials targeting amyloid and population screening,” Dr. Faux and co-authors said in Scientific Reports.
Dr. Faux and colleagues used a Random Forest approach to build models for CSF Abeta1-42 using blood biomarkers and other variables.
They found that a model incorporating age, APOEe4 carrier status, and a number of plasma protein levels predicted Abeta1-42 normal/abnormalstatus with an AUC, sensitivity and specificity of 0.84, 0.78 and 0.73 respectively.
In a model they said was more suitable for clinical application, they narrowed down the variables to 4 plasma analytes and APOEe4 carrier status, which had an AUC, sensitivity, and specificity of 0.81, 0.81 and 0.64 respectively.
They validated the models on a cohort of individuals in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a large, longitudinal, multicenter study.
Patients with mild cognitive impairment with predicted abnormal CSF Abeta1-42 levels indeed did transition to a diagnosis of Alzheimer’s disease more quickly than those with predicted normal levels, according to investigators.
That helps provide “strong evidence” that the blood-based model is generalizable, robust, and could help stratify patients based on risk of progressing to Alzheimer’s disease, they said in their report.
Dr. Faux and colleagues declared no conflicts of interest related to the research.
SOURCE: Goudey B, et al. Sci Rep. 2019 Mar 10. doi: 10.1101/190207v3.
A recently developed blood-based signature can help predict the status of an early Alzheimer’s disease risk indicator with high accuracy, investigators are reporting.
By analyzing as few as four proteins, the machine learning-derived test can predict the status of cerebrospinal fluid (CSF) amyloid beta1-42 (Abeta1-42), according to Noel G. Faux, PHD, of IBM Australia and the University of Melbourne, and co-investigators.
While shifts in Abeta1-42 may signal the presence of disease long before significant cognitive decline is clinically apparent, collection of CSF is highly invasive and expensive, Faux and investigators said in their report.
By contrast, blood biomarkers could prove to be a useful alternative not only to invasive lumbar punctures, they said, but also to the positron emission tomography (PET) evaluation of Abeta1-42, which is expensive and limited in some regions.
“In conjunction with biomarkers for neocortical amyloid burden, the CSF Abeta1-42biomarkers presented in this work may help yield a cheap, non-invasive tool for both improving clinical trials targeting amyloid and population screening,” Dr. Faux and co-authors said in Scientific Reports.
Dr. Faux and colleagues used a Random Forest approach to build models for CSF Abeta1-42 using blood biomarkers and other variables.
They found that a model incorporating age, APOEe4 carrier status, and a number of plasma protein levels predicted Abeta1-42 normal/abnormalstatus with an AUC, sensitivity and specificity of 0.84, 0.78 and 0.73 respectively.
In a model they said was more suitable for clinical application, they narrowed down the variables to 4 plasma analytes and APOEe4 carrier status, which had an AUC, sensitivity, and specificity of 0.81, 0.81 and 0.64 respectively.
They validated the models on a cohort of individuals in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a large, longitudinal, multicenter study.
Patients with mild cognitive impairment with predicted abnormal CSF Abeta1-42 levels indeed did transition to a diagnosis of Alzheimer’s disease more quickly than those with predicted normal levels, according to investigators.
That helps provide “strong evidence” that the blood-based model is generalizable, robust, and could help stratify patients based on risk of progressing to Alzheimer’s disease, they said in their report.
Dr. Faux and colleagues declared no conflicts of interest related to the research.
SOURCE: Goudey B, et al. Sci Rep. 2019 Mar 10. doi: 10.1101/190207v3.
FROM SCIENTIFIC REPORTS
Key clinical point: A blood-based signature can help predict the status of an early Alzheimer’s disease risk indicator.
Major finding:
Study details: Machine learning analysis of blood biomarkers and other variables in a validation cohort of 198 individuals.
Disclosures: The study authors declared no conflicts of interest.
Source: Goudey B, et al. Sci Rep. 2019 Mar 10. doi: 10.1101/190207v3.
Total plasma tau correlates with dementia onset, Alzheimer’s disease
The total tau level in blood plasma appears to predict both onset and progression of dementia and could be used to help refine research cohorts.
Blood samples from two large dementia research cohorts confirmed the finding: Each standard deviation in plasma tau above the median is associated with a 29% greater risk of incident all-cause dementia and a 35%increase in the risk of incident Alzheimer’s disease, Matthew P. Pase, PhD and colleagues wrote in JAMA Neurology. It also correlated positively with some neuropathological aspects of dementia: smaller hippocampus and a higher burden of neurofibrillary tangles in the medial temporal lobe, said Dr. Pase of The Florey Institute for Neuroscience and Mental Health. Victoria, Australia.
Plasma tau isn’t the highly sought Holy Grail of a simple Alzheimer’s blood test. But the finding could benefit the research world. As a study entry criteria, it could substantially decrease the number of subjects needed to validate an outcome of either all-cause dementia or Alzheimer’s disease. Abnormal tau is also a required finding for an Alzheimer’s diagnosis in revised NIA-AA Research Framework. And, the authors noted, although plasma tau wasn’t quite as accurate a predictor as CSF tau, a needle in the arm would be much more acceptable to many more patients than a lumbar puncture.
“Whereas we do not expect plasma t-tau cutoffs to enhance diagnostic certainty for any single patient, our results suggest that plasma t-tau could be associated with improved risk stratification at a population level, targeting persons for inclusion in prevention trials, thus improving the power and precision of clinical trials and potentially accelerating therapeutic pipelines and drug discovery,” the team wrote.
The study drew on stored plasma samples from subjects enrolled in the Framingham Heart Study (1,453) and the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France (367).
The Framingham cohort was followed for up to 10 years between baseline examination to incident event (median 6 years).
Over that time, 134 (9.2%) cases of dementia developed; most of these (105) were due possible, probable, or definite Alzheimer’s.
Plasma tau levels rose linearly as the cohort aged. Higher plasma t-tau levels were associated with proven AD risk factors, including female sex, lower education, and higher vascular risk factors. They did not differ by apolipoprotein epsilon 4 status (APOEe4).
After adjusting for age and sex, each stand deviation unit increase in the log of tau was associated with a 29% greater risk of incident all-cause dementia, and a 35% increase in the risk of incident Alzheimer’s dementia. Subjects with tau levels above the median had a 62% increased risk of all-cause dementia and a 76% greater risk of AD. Adding APOEe4 status and vascular risk factors to the analysis didn’t alter the associations.
“Plasma t-tau level improved risk discrimination for all dementia and AD dementia beyond age and sex,” the investigators wrote. “[It] was associated with improved risk discrimination … in both APOEe4 carriers and noncarriers.”
In a hypothetical 5-year clinical trial, enrolling subjects with total plasma tau greater than the median could reduce the estimated necessary sample size by 38% for an outcome of all-cause dementia and by 50% for one of Alzheimer’s. Selecting those with both elevated plasma tau and APOEe4 carriage could reduce the required sample by 69% for all-cause dementia outcomes and by 80% for Alzheimer’s outcomes.
In the neuropathologic study, each standard deviation unit increase was associated with more neurofibrillary tangles in the medial temporal lobe, more microinfarcts, and smaller hippocampal volume. There was no association with amyloid plaque in any brain region.
Subjects in the Memento study had a meant of 4 years of follow-up. Over that time, there were 76 cases of incident dementia, 55 of which were probable Alzheimer’s.
Each standard deviation unit increase was associated with a nonsignificant 14% greater risk of all-cause dementia and a significant 54% increase in the risk of incident Alzheimer’s.
CSF was drawn on the same day as plasma in 140 of these subjects. The addition of CSF boosted the predictive value; each standard deviation increase more than doubled the risk of both Alzheimer’s (HR 2.33). Each standard deviation unit increase in CSF t-tau increased the risk by 2.14.
“Plasma t-tau was weakly correlated with CSF t-tau in our study. This finding is consistent
with previous studies showing that the associations of plasma t-tau with CSF t-tau have been weak or nonexistent,” the authors wrote. But, “Despite a weak correlation between plasma and CSF t-tau, plasma t-tau was at least as strongly associated with the development of incident AD dementia.”
“Use of plasma t-tau in this manner could be likened to the measurement of the APOEe4 allele, which is not a biomarker of AD pathology providing diagnostic certainty for AD dementia but is still routinely used to power clinical trials by selecting at-risk individuals,” they concluded.
Dr. Pase had no financial disclosures.
SOURCE: Pase, M et al JAMA Neurol 2019 doi:10.1001/jamaneurol.2018.4666
The total tau level in blood plasma appears to predict both onset and progression of dementia and could be used to help refine research cohorts.
Blood samples from two large dementia research cohorts confirmed the finding: Each standard deviation in plasma tau above the median is associated with a 29% greater risk of incident all-cause dementia and a 35%increase in the risk of incident Alzheimer’s disease, Matthew P. Pase, PhD and colleagues wrote in JAMA Neurology. It also correlated positively with some neuropathological aspects of dementia: smaller hippocampus and a higher burden of neurofibrillary tangles in the medial temporal lobe, said Dr. Pase of The Florey Institute for Neuroscience and Mental Health. Victoria, Australia.
Plasma tau isn’t the highly sought Holy Grail of a simple Alzheimer’s blood test. But the finding could benefit the research world. As a study entry criteria, it could substantially decrease the number of subjects needed to validate an outcome of either all-cause dementia or Alzheimer’s disease. Abnormal tau is also a required finding for an Alzheimer’s diagnosis in revised NIA-AA Research Framework. And, the authors noted, although plasma tau wasn’t quite as accurate a predictor as CSF tau, a needle in the arm would be much more acceptable to many more patients than a lumbar puncture.
“Whereas we do not expect plasma t-tau cutoffs to enhance diagnostic certainty for any single patient, our results suggest that plasma t-tau could be associated with improved risk stratification at a population level, targeting persons for inclusion in prevention trials, thus improving the power and precision of clinical trials and potentially accelerating therapeutic pipelines and drug discovery,” the team wrote.
The study drew on stored plasma samples from subjects enrolled in the Framingham Heart Study (1,453) and the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France (367).
The Framingham cohort was followed for up to 10 years between baseline examination to incident event (median 6 years).
Over that time, 134 (9.2%) cases of dementia developed; most of these (105) were due possible, probable, or definite Alzheimer’s.
Plasma tau levels rose linearly as the cohort aged. Higher plasma t-tau levels were associated with proven AD risk factors, including female sex, lower education, and higher vascular risk factors. They did not differ by apolipoprotein epsilon 4 status (APOEe4).
After adjusting for age and sex, each stand deviation unit increase in the log of tau was associated with a 29% greater risk of incident all-cause dementia, and a 35% increase in the risk of incident Alzheimer’s dementia. Subjects with tau levels above the median had a 62% increased risk of all-cause dementia and a 76% greater risk of AD. Adding APOEe4 status and vascular risk factors to the analysis didn’t alter the associations.
“Plasma t-tau level improved risk discrimination for all dementia and AD dementia beyond age and sex,” the investigators wrote. “[It] was associated with improved risk discrimination … in both APOEe4 carriers and noncarriers.”
In a hypothetical 5-year clinical trial, enrolling subjects with total plasma tau greater than the median could reduce the estimated necessary sample size by 38% for an outcome of all-cause dementia and by 50% for one of Alzheimer’s. Selecting those with both elevated plasma tau and APOEe4 carriage could reduce the required sample by 69% for all-cause dementia outcomes and by 80% for Alzheimer’s outcomes.
In the neuropathologic study, each standard deviation unit increase was associated with more neurofibrillary tangles in the medial temporal lobe, more microinfarcts, and smaller hippocampal volume. There was no association with amyloid plaque in any brain region.
Subjects in the Memento study had a meant of 4 years of follow-up. Over that time, there were 76 cases of incident dementia, 55 of which were probable Alzheimer’s.
Each standard deviation unit increase was associated with a nonsignificant 14% greater risk of all-cause dementia and a significant 54% increase in the risk of incident Alzheimer’s.
CSF was drawn on the same day as plasma in 140 of these subjects. The addition of CSF boosted the predictive value; each standard deviation increase more than doubled the risk of both Alzheimer’s (HR 2.33). Each standard deviation unit increase in CSF t-tau increased the risk by 2.14.
“Plasma t-tau was weakly correlated with CSF t-tau in our study. This finding is consistent
with previous studies showing that the associations of plasma t-tau with CSF t-tau have been weak or nonexistent,” the authors wrote. But, “Despite a weak correlation between plasma and CSF t-tau, plasma t-tau was at least as strongly associated with the development of incident AD dementia.”
“Use of plasma t-tau in this manner could be likened to the measurement of the APOEe4 allele, which is not a biomarker of AD pathology providing diagnostic certainty for AD dementia but is still routinely used to power clinical trials by selecting at-risk individuals,” they concluded.
Dr. Pase had no financial disclosures.
SOURCE: Pase, M et al JAMA Neurol 2019 doi:10.1001/jamaneurol.2018.4666
The total tau level in blood plasma appears to predict both onset and progression of dementia and could be used to help refine research cohorts.
Blood samples from two large dementia research cohorts confirmed the finding: Each standard deviation in plasma tau above the median is associated with a 29% greater risk of incident all-cause dementia and a 35%increase in the risk of incident Alzheimer’s disease, Matthew P. Pase, PhD and colleagues wrote in JAMA Neurology. It also correlated positively with some neuropathological aspects of dementia: smaller hippocampus and a higher burden of neurofibrillary tangles in the medial temporal lobe, said Dr. Pase of The Florey Institute for Neuroscience and Mental Health. Victoria, Australia.
Plasma tau isn’t the highly sought Holy Grail of a simple Alzheimer’s blood test. But the finding could benefit the research world. As a study entry criteria, it could substantially decrease the number of subjects needed to validate an outcome of either all-cause dementia or Alzheimer’s disease. Abnormal tau is also a required finding for an Alzheimer’s diagnosis in revised NIA-AA Research Framework. And, the authors noted, although plasma tau wasn’t quite as accurate a predictor as CSF tau, a needle in the arm would be much more acceptable to many more patients than a lumbar puncture.
“Whereas we do not expect plasma t-tau cutoffs to enhance diagnostic certainty for any single patient, our results suggest that plasma t-tau could be associated with improved risk stratification at a population level, targeting persons for inclusion in prevention trials, thus improving the power and precision of clinical trials and potentially accelerating therapeutic pipelines and drug discovery,” the team wrote.
The study drew on stored plasma samples from subjects enrolled in the Framingham Heart Study (1,453) and the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France (367).
The Framingham cohort was followed for up to 10 years between baseline examination to incident event (median 6 years).
Over that time, 134 (9.2%) cases of dementia developed; most of these (105) were due possible, probable, or definite Alzheimer’s.
Plasma tau levels rose linearly as the cohort aged. Higher plasma t-tau levels were associated with proven AD risk factors, including female sex, lower education, and higher vascular risk factors. They did not differ by apolipoprotein epsilon 4 status (APOEe4).
After adjusting for age and sex, each stand deviation unit increase in the log of tau was associated with a 29% greater risk of incident all-cause dementia, and a 35% increase in the risk of incident Alzheimer’s dementia. Subjects with tau levels above the median had a 62% increased risk of all-cause dementia and a 76% greater risk of AD. Adding APOEe4 status and vascular risk factors to the analysis didn’t alter the associations.
“Plasma t-tau level improved risk discrimination for all dementia and AD dementia beyond age and sex,” the investigators wrote. “[It] was associated with improved risk discrimination … in both APOEe4 carriers and noncarriers.”
In a hypothetical 5-year clinical trial, enrolling subjects with total plasma tau greater than the median could reduce the estimated necessary sample size by 38% for an outcome of all-cause dementia and by 50% for one of Alzheimer’s. Selecting those with both elevated plasma tau and APOEe4 carriage could reduce the required sample by 69% for all-cause dementia outcomes and by 80% for Alzheimer’s outcomes.
In the neuropathologic study, each standard deviation unit increase was associated with more neurofibrillary tangles in the medial temporal lobe, more microinfarcts, and smaller hippocampal volume. There was no association with amyloid plaque in any brain region.
Subjects in the Memento study had a meant of 4 years of follow-up. Over that time, there were 76 cases of incident dementia, 55 of which were probable Alzheimer’s.
Each standard deviation unit increase was associated with a nonsignificant 14% greater risk of all-cause dementia and a significant 54% increase in the risk of incident Alzheimer’s.
CSF was drawn on the same day as plasma in 140 of these subjects. The addition of CSF boosted the predictive value; each standard deviation increase more than doubled the risk of both Alzheimer’s (HR 2.33). Each standard deviation unit increase in CSF t-tau increased the risk by 2.14.
“Plasma t-tau was weakly correlated with CSF t-tau in our study. This finding is consistent
with previous studies showing that the associations of plasma t-tau with CSF t-tau have been weak or nonexistent,” the authors wrote. But, “Despite a weak correlation between plasma and CSF t-tau, plasma t-tau was at least as strongly associated with the development of incident AD dementia.”
“Use of plasma t-tau in this manner could be likened to the measurement of the APOEe4 allele, which is not a biomarker of AD pathology providing diagnostic certainty for AD dementia but is still routinely used to power clinical trials by selecting at-risk individuals,” they concluded.
Dr. Pase had no financial disclosures.
SOURCE: Pase, M et al JAMA Neurol 2019 doi:10.1001/jamaneurol.2018.4666
FROM JAMA NEUROLOGY
Noncardiac surgery has 7% covert stroke rate in elderly
HONOLULU – Covert strokes are relatively common in elderly patients who undergo noncardiac surgery, with a 7% incidence among a group of prospectively followed but generally unselected patients in a multicenter, international study.
By definition, these covert strokes were acutely asymptomatic, but showed evidence of clinical effects during the subsequent year. Twelve months after surgery, patients with acute, perioperative covert strokes found by systematic collection of postoperative MRI brain scans had a twofold increased rate of cognitive decline and a greater than twofold increased rate of delirium, compared with the patients who did not have evidence of a covert stroke, Marko Mrkobrada, MD, said at the International Stroke Conference sponsored by the American Heart Association.
The message from these findings is that, when elderly patients exhibit confusion or delirium after noncardiac surgery, their physicians should have a high index of suspicion that a covert stroke may have occurred, Dr. Mrkobrada said in a video interview. It’s possible that typical stroke symptoms do not appear in many of the covert stroke patients because they are masked in the immediate postoperative period, he added.
Right now, the only way to screen for a covert stroke is with a brain MR, a test that generally costs several hundred dollars, which is too expensive for routine screening. Dr. Mrkobrada said that his team hopes further study will identify a biomarker that can flag patients with a covert stroke at a lower cost. For example, colleagues of Dr. Mrkobrada have successfully used high-sensitivity troponin T, a biomarker of myocardial injury, to identify patients who have myocardial injury after noncardiac surgery (MINS; JAMA. 2017 April 25;371[16]:1642-51). Study results also established that treating MINS patients with dabigatran improved their long-term clinical outcomes (Lancet. 2018 June 9;391[10137]:2325-34).
Covert stroke after noncardiac surgery “is the same concept” as MINS, said Dr. Mrkobrada, a researcher at the London Health Sciences Centre in Canada. “We find strokes that do not get picked up after noncardiac surgery just like MIs that are not picked up,” he said. It’s also possible that certain interventions may improve outcomes in patients with covert strokes, just as they have helped MINS patients, he suggested. Potentially helpful interventions could include aspirin, a statin, and improved blood pressure control. A major goal for his research group is finding a biomarker that makes diagnosing covert stroke as easy as using high sensitivity troponin T to diagnose MINS.
The NeuroVISION (Detection and Neurological Impact of Cerebrovascular Events In Noncardiac Surgery Patients: A Cohort EvaluatioN) study enrolled and tested 1,114 people aged 65 years or older scheduled for elective noncardiac surgery anticipated to keep them hospitalized for at least 2 days at any of 12 participating centers in nine countries. Patients underwent cognitive function testing before surgery and had a brain MR scan 2-9 days after surgery, and they were excluded if they developed an overt stroke prior to the scan. Patients underwent a second round of cognitive testing a year after surgery. Patients averaged 73 years old.
The screening MR scans identified covert strokes in 78 of the study subjects (7%). The 1-year cognitive tests showed measurable drops in cognitive function in 42% of those who had experience covert strokes and in 29% of everyone else. Those rates translated to a doubled odds ratio for cognitive decline after covert stroke, compared with people without covert stroke after adjustment for baseline between-group differences, a highly statistically significant between-group difference for the study’s primary endpoint. Delirium occurred 2.2-fold more often in the covert stroke patients after adjustment, and overt strokes during 1-year follow-up were 4.1-fold more common patients who’d experienced a covert stroke, compared with everyone else, after adjustment, Dr. Mrkobrada reported. NeuroVISION is the first large-scale study to assess the incidence and associations of covert strokes after noncardiac surgery, he noted.
SOURCE: Mrkobrada M. ISC 2019, Late-Breaking Abstract LB18.
HONOLULU – Covert strokes are relatively common in elderly patients who undergo noncardiac surgery, with a 7% incidence among a group of prospectively followed but generally unselected patients in a multicenter, international study.
By definition, these covert strokes were acutely asymptomatic, but showed evidence of clinical effects during the subsequent year. Twelve months after surgery, patients with acute, perioperative covert strokes found by systematic collection of postoperative MRI brain scans had a twofold increased rate of cognitive decline and a greater than twofold increased rate of delirium, compared with the patients who did not have evidence of a covert stroke, Marko Mrkobrada, MD, said at the International Stroke Conference sponsored by the American Heart Association.
The message from these findings is that, when elderly patients exhibit confusion or delirium after noncardiac surgery, their physicians should have a high index of suspicion that a covert stroke may have occurred, Dr. Mrkobrada said in a video interview. It’s possible that typical stroke symptoms do not appear in many of the covert stroke patients because they are masked in the immediate postoperative period, he added.
Right now, the only way to screen for a covert stroke is with a brain MR, a test that generally costs several hundred dollars, which is too expensive for routine screening. Dr. Mrkobrada said that his team hopes further study will identify a biomarker that can flag patients with a covert stroke at a lower cost. For example, colleagues of Dr. Mrkobrada have successfully used high-sensitivity troponin T, a biomarker of myocardial injury, to identify patients who have myocardial injury after noncardiac surgery (MINS; JAMA. 2017 April 25;371[16]:1642-51). Study results also established that treating MINS patients with dabigatran improved their long-term clinical outcomes (Lancet. 2018 June 9;391[10137]:2325-34).
Covert stroke after noncardiac surgery “is the same concept” as MINS, said Dr. Mrkobrada, a researcher at the London Health Sciences Centre in Canada. “We find strokes that do not get picked up after noncardiac surgery just like MIs that are not picked up,” he said. It’s also possible that certain interventions may improve outcomes in patients with covert strokes, just as they have helped MINS patients, he suggested. Potentially helpful interventions could include aspirin, a statin, and improved blood pressure control. A major goal for his research group is finding a biomarker that makes diagnosing covert stroke as easy as using high sensitivity troponin T to diagnose MINS.
The NeuroVISION (Detection and Neurological Impact of Cerebrovascular Events In Noncardiac Surgery Patients: A Cohort EvaluatioN) study enrolled and tested 1,114 people aged 65 years or older scheduled for elective noncardiac surgery anticipated to keep them hospitalized for at least 2 days at any of 12 participating centers in nine countries. Patients underwent cognitive function testing before surgery and had a brain MR scan 2-9 days after surgery, and they were excluded if they developed an overt stroke prior to the scan. Patients underwent a second round of cognitive testing a year after surgery. Patients averaged 73 years old.
The screening MR scans identified covert strokes in 78 of the study subjects (7%). The 1-year cognitive tests showed measurable drops in cognitive function in 42% of those who had experience covert strokes and in 29% of everyone else. Those rates translated to a doubled odds ratio for cognitive decline after covert stroke, compared with people without covert stroke after adjustment for baseline between-group differences, a highly statistically significant between-group difference for the study’s primary endpoint. Delirium occurred 2.2-fold more often in the covert stroke patients after adjustment, and overt strokes during 1-year follow-up were 4.1-fold more common patients who’d experienced a covert stroke, compared with everyone else, after adjustment, Dr. Mrkobrada reported. NeuroVISION is the first large-scale study to assess the incidence and associations of covert strokes after noncardiac surgery, he noted.
SOURCE: Mrkobrada M. ISC 2019, Late-Breaking Abstract LB18.
HONOLULU – Covert strokes are relatively common in elderly patients who undergo noncardiac surgery, with a 7% incidence among a group of prospectively followed but generally unselected patients in a multicenter, international study.
By definition, these covert strokes were acutely asymptomatic, but showed evidence of clinical effects during the subsequent year. Twelve months after surgery, patients with acute, perioperative covert strokes found by systematic collection of postoperative MRI brain scans had a twofold increased rate of cognitive decline and a greater than twofold increased rate of delirium, compared with the patients who did not have evidence of a covert stroke, Marko Mrkobrada, MD, said at the International Stroke Conference sponsored by the American Heart Association.
The message from these findings is that, when elderly patients exhibit confusion or delirium after noncardiac surgery, their physicians should have a high index of suspicion that a covert stroke may have occurred, Dr. Mrkobrada said in a video interview. It’s possible that typical stroke symptoms do not appear in many of the covert stroke patients because they are masked in the immediate postoperative period, he added.
Right now, the only way to screen for a covert stroke is with a brain MR, a test that generally costs several hundred dollars, which is too expensive for routine screening. Dr. Mrkobrada said that his team hopes further study will identify a biomarker that can flag patients with a covert stroke at a lower cost. For example, colleagues of Dr. Mrkobrada have successfully used high-sensitivity troponin T, a biomarker of myocardial injury, to identify patients who have myocardial injury after noncardiac surgery (MINS; JAMA. 2017 April 25;371[16]:1642-51). Study results also established that treating MINS patients with dabigatran improved their long-term clinical outcomes (Lancet. 2018 June 9;391[10137]:2325-34).
Covert stroke after noncardiac surgery “is the same concept” as MINS, said Dr. Mrkobrada, a researcher at the London Health Sciences Centre in Canada. “We find strokes that do not get picked up after noncardiac surgery just like MIs that are not picked up,” he said. It’s also possible that certain interventions may improve outcomes in patients with covert strokes, just as they have helped MINS patients, he suggested. Potentially helpful interventions could include aspirin, a statin, and improved blood pressure control. A major goal for his research group is finding a biomarker that makes diagnosing covert stroke as easy as using high sensitivity troponin T to diagnose MINS.
The NeuroVISION (Detection and Neurological Impact of Cerebrovascular Events In Noncardiac Surgery Patients: A Cohort EvaluatioN) study enrolled and tested 1,114 people aged 65 years or older scheduled for elective noncardiac surgery anticipated to keep them hospitalized for at least 2 days at any of 12 participating centers in nine countries. Patients underwent cognitive function testing before surgery and had a brain MR scan 2-9 days after surgery, and they were excluded if they developed an overt stroke prior to the scan. Patients underwent a second round of cognitive testing a year after surgery. Patients averaged 73 years old.
The screening MR scans identified covert strokes in 78 of the study subjects (7%). The 1-year cognitive tests showed measurable drops in cognitive function in 42% of those who had experience covert strokes and in 29% of everyone else. Those rates translated to a doubled odds ratio for cognitive decline after covert stroke, compared with people without covert stroke after adjustment for baseline between-group differences, a highly statistically significant between-group difference for the study’s primary endpoint. Delirium occurred 2.2-fold more often in the covert stroke patients after adjustment, and overt strokes during 1-year follow-up were 4.1-fold more common patients who’d experienced a covert stroke, compared with everyone else, after adjustment, Dr. Mrkobrada reported. NeuroVISION is the first large-scale study to assess the incidence and associations of covert strokes after noncardiac surgery, he noted.
SOURCE: Mrkobrada M. ISC 2019, Late-Breaking Abstract LB18.
REPORTING FROM ISC 2019
Key clinical point:
Major finding: Elderly patients who underwent noncardiac surgery had a 7% incidence of covert stroke.
Study details: NeuroVISION, a prospective, multicenter, observational study with 1,114 patients.
Disclosures: NeuroVISION did not receive commercial funding. Dr. Mrkobrada had no disclosures.
Source: Mrkobrada M. ISC 2019, Late-Breaking Abstract LB18.
FDA issues warnings to companies selling illegal Alzheimer’s treatments
The Food and Drug Administration has issued warning letters to 12 companies and advisory letters to 5 companies illegally selling more than 58 products claiming to treat Alzheimer’s disease.
The products, many of which are marketed as dietary supplements, are being sold in a variety of forms, including tablets, capsules, and oils. These drugs are either unapproved or mislabeled and claim to prevent, treat, or cure Alzheimer’s disease, as well as a number of other serious diseases and health conditions, in violation of the Federal Food, Drug, and Cosmetic Act.
“Alzheimer’s is a challenging disease that, unfortunately, has no cure. Any products making unproven drug claims could mislead consumers to believe that such therapies exist and keep them from accessing therapies that are known to help support the symptoms of the disease, or worse, as some fraudulent treatments can cause serious or even fatal injuries,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
In an additional statement, Dr. Gottlieb detailed several new strategies for improving the safety and accuracy of dietary supplements, including efforts to more rapidly communicate to the public potential safety issues with dietary supplement products and to establish a flexible regulatory framework that promotes innovation and upholds product safety.
The Food and Drug Administration has issued warning letters to 12 companies and advisory letters to 5 companies illegally selling more than 58 products claiming to treat Alzheimer’s disease.
The products, many of which are marketed as dietary supplements, are being sold in a variety of forms, including tablets, capsules, and oils. These drugs are either unapproved or mislabeled and claim to prevent, treat, or cure Alzheimer’s disease, as well as a number of other serious diseases and health conditions, in violation of the Federal Food, Drug, and Cosmetic Act.
“Alzheimer’s is a challenging disease that, unfortunately, has no cure. Any products making unproven drug claims could mislead consumers to believe that such therapies exist and keep them from accessing therapies that are known to help support the symptoms of the disease, or worse, as some fraudulent treatments can cause serious or even fatal injuries,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
In an additional statement, Dr. Gottlieb detailed several new strategies for improving the safety and accuracy of dietary supplements, including efforts to more rapidly communicate to the public potential safety issues with dietary supplement products and to establish a flexible regulatory framework that promotes innovation and upholds product safety.
The Food and Drug Administration has issued warning letters to 12 companies and advisory letters to 5 companies illegally selling more than 58 products claiming to treat Alzheimer’s disease.
The products, many of which are marketed as dietary supplements, are being sold in a variety of forms, including tablets, capsules, and oils. These drugs are either unapproved or mislabeled and claim to prevent, treat, or cure Alzheimer’s disease, as well as a number of other serious diseases and health conditions, in violation of the Federal Food, Drug, and Cosmetic Act.
“Alzheimer’s is a challenging disease that, unfortunately, has no cure. Any products making unproven drug claims could mislead consumers to believe that such therapies exist and keep them from accessing therapies that are known to help support the symptoms of the disease, or worse, as some fraudulent treatments can cause serious or even fatal injuries,” FDA Commissioner Scott Gottlieb, MD, said in a press release.
In an additional statement, Dr. Gottlieb detailed several new strategies for improving the safety and accuracy of dietary supplements, including efforts to more rapidly communicate to the public potential safety issues with dietary supplement products and to establish a flexible regulatory framework that promotes innovation and upholds product safety.
Novel plasma biomarkers may predict preclinical Alzheimer’s disease
, researchers reported in Science Advances.
“To our knowledge, this is the first time that a multianalyte plasma biomarker panel for an Alzheimer’s disease–related phenotype has been found and independently replicated by a nontargeted mass spectrometry approach,” said Nicholas J. Ashton, PhD, of King’s College London and the University of Gothenburg in Sweden, and his research colleagues.
Blood-based measures that predict amyloid-beta burden in preclinical Alzheimer’s disease have the potential to help investigators conduct clinical trials and aid in diagnostic management. However, this novel approach needs to be validated and translated “to a simpler automated platform suitable for wider utility,” the investigators noted. In addition, it is unclear whether their classifier can track changes in amyloid-beta or differentiate between other diseases with amyloid-beta pathology.
Advances in mass spectrometry technology have renewed interest in the analysis of plasma proteins in patients with various diseases. To assess whether proteomic discovery in plasma can help predict amyloid-beta burden in preclinical Alzheimer’s disease, Dr. Ashton and his colleagues studied 238 cognitively unimpaired individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH). The participants had undergone PET to determine their amyloid-beta status. In the AIBL cohort (n = 144), 100 participants were amyloid-beta negative, and 44 were amyloid-beta positive. In the KARVIAH cohort (n = 94), 59 participants were amyloid-beta negative, and 35 were amyloid-beta positive. There were significantly more APOE4 carriers in the amyloid-beta–positive groups than in the amyloid-beta–negative groups. In addition, the amyloid-beta–positive groups tended to be older.
A support vector machine analysis created classifiers predicting amyloid-beta positivity in the AIBL cohort using demographics, proteins, or both. The researchers then tested each classifier in the KARVIAH dataset to identify which model best predicted amyloid-beta positivity. The optimal model included 10 protein features (prothrombin, adhesion G protein–coupled receptor, amyloid-beta A4 protein, NGN2, DNAH10, REST, NfL, RPS6KA3, GPSM2, FHAD1) and two demographic features (APOE4 count and age).
The classifier achieved a testing area under the receiver operator characteristic curve of 0.891 in the KARVIAH cohort to predict amyloid-beta positivity in cognitively unimpaired individuals with a sensitivity of 0.78 and specificity of 0.77.
The 10 protein features “represent a diverse array of pathways,” and the highest ranked feature was the serine protease prothrombin, which is a precursor to thrombin, the authors noted. “Multiple lines of evidence support that cerebrovascular disease may play a role in AD and that amyloid-beta may be involved in thrombosis, fibrinolysis, and inflammation via its interaction with the coagulation cascade,” the researchers wrote.
Two of the biomarkers – amyloid-beta A4 protein and NfL – have been examined in prior research and had a greater effect size in a secondary analysis that included participants with mild cognitive impairment and Alzheimer’s disease. This finding confirms “their connection with the more established disease state,” Dr. Ashton and colleagues said. In the secondary analysis, the optimal classifier included one demographic factor (APOE4 count) and nine protein features, eight of which also were used in the cognitively unimpaired classifier.
The study was funded in part by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, and many authors reported additional research support from various institutions. One author is an employee of Johnson & Johnson and a named inventor on unrelated biomarker intellectual property owned by Proteome Science and King’s College London.
SOURCE: Ashton NJ et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aau7220.
, researchers reported in Science Advances.
“To our knowledge, this is the first time that a multianalyte plasma biomarker panel for an Alzheimer’s disease–related phenotype has been found and independently replicated by a nontargeted mass spectrometry approach,” said Nicholas J. Ashton, PhD, of King’s College London and the University of Gothenburg in Sweden, and his research colleagues.
Blood-based measures that predict amyloid-beta burden in preclinical Alzheimer’s disease have the potential to help investigators conduct clinical trials and aid in diagnostic management. However, this novel approach needs to be validated and translated “to a simpler automated platform suitable for wider utility,” the investigators noted. In addition, it is unclear whether their classifier can track changes in amyloid-beta or differentiate between other diseases with amyloid-beta pathology.
Advances in mass spectrometry technology have renewed interest in the analysis of plasma proteins in patients with various diseases. To assess whether proteomic discovery in plasma can help predict amyloid-beta burden in preclinical Alzheimer’s disease, Dr. Ashton and his colleagues studied 238 cognitively unimpaired individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH). The participants had undergone PET to determine their amyloid-beta status. In the AIBL cohort (n = 144), 100 participants were amyloid-beta negative, and 44 were amyloid-beta positive. In the KARVIAH cohort (n = 94), 59 participants were amyloid-beta negative, and 35 were amyloid-beta positive. There were significantly more APOE4 carriers in the amyloid-beta–positive groups than in the amyloid-beta–negative groups. In addition, the amyloid-beta–positive groups tended to be older.
A support vector machine analysis created classifiers predicting amyloid-beta positivity in the AIBL cohort using demographics, proteins, or both. The researchers then tested each classifier in the KARVIAH dataset to identify which model best predicted amyloid-beta positivity. The optimal model included 10 protein features (prothrombin, adhesion G protein–coupled receptor, amyloid-beta A4 protein, NGN2, DNAH10, REST, NfL, RPS6KA3, GPSM2, FHAD1) and two demographic features (APOE4 count and age).
The classifier achieved a testing area under the receiver operator characteristic curve of 0.891 in the KARVIAH cohort to predict amyloid-beta positivity in cognitively unimpaired individuals with a sensitivity of 0.78 and specificity of 0.77.
The 10 protein features “represent a diverse array of pathways,” and the highest ranked feature was the serine protease prothrombin, which is a precursor to thrombin, the authors noted. “Multiple lines of evidence support that cerebrovascular disease may play a role in AD and that amyloid-beta may be involved in thrombosis, fibrinolysis, and inflammation via its interaction with the coagulation cascade,” the researchers wrote.
Two of the biomarkers – amyloid-beta A4 protein and NfL – have been examined in prior research and had a greater effect size in a secondary analysis that included participants with mild cognitive impairment and Alzheimer’s disease. This finding confirms “their connection with the more established disease state,” Dr. Ashton and colleagues said. In the secondary analysis, the optimal classifier included one demographic factor (APOE4 count) and nine protein features, eight of which also were used in the cognitively unimpaired classifier.
The study was funded in part by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, and many authors reported additional research support from various institutions. One author is an employee of Johnson & Johnson and a named inventor on unrelated biomarker intellectual property owned by Proteome Science and King’s College London.
SOURCE: Ashton NJ et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aau7220.
, researchers reported in Science Advances.
“To our knowledge, this is the first time that a multianalyte plasma biomarker panel for an Alzheimer’s disease–related phenotype has been found and independently replicated by a nontargeted mass spectrometry approach,” said Nicholas J. Ashton, PhD, of King’s College London and the University of Gothenburg in Sweden, and his research colleagues.
Blood-based measures that predict amyloid-beta burden in preclinical Alzheimer’s disease have the potential to help investigators conduct clinical trials and aid in diagnostic management. However, this novel approach needs to be validated and translated “to a simpler automated platform suitable for wider utility,” the investigators noted. In addition, it is unclear whether their classifier can track changes in amyloid-beta or differentiate between other diseases with amyloid-beta pathology.
Advances in mass spectrometry technology have renewed interest in the analysis of plasma proteins in patients with various diseases. To assess whether proteomic discovery in plasma can help predict amyloid-beta burden in preclinical Alzheimer’s disease, Dr. Ashton and his colleagues studied 238 cognitively unimpaired individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH). The participants had undergone PET to determine their amyloid-beta status. In the AIBL cohort (n = 144), 100 participants were amyloid-beta negative, and 44 were amyloid-beta positive. In the KARVIAH cohort (n = 94), 59 participants were amyloid-beta negative, and 35 were amyloid-beta positive. There were significantly more APOE4 carriers in the amyloid-beta–positive groups than in the amyloid-beta–negative groups. In addition, the amyloid-beta–positive groups tended to be older.
A support vector machine analysis created classifiers predicting amyloid-beta positivity in the AIBL cohort using demographics, proteins, or both. The researchers then tested each classifier in the KARVIAH dataset to identify which model best predicted amyloid-beta positivity. The optimal model included 10 protein features (prothrombin, adhesion G protein–coupled receptor, amyloid-beta A4 protein, NGN2, DNAH10, REST, NfL, RPS6KA3, GPSM2, FHAD1) and two demographic features (APOE4 count and age).
The classifier achieved a testing area under the receiver operator characteristic curve of 0.891 in the KARVIAH cohort to predict amyloid-beta positivity in cognitively unimpaired individuals with a sensitivity of 0.78 and specificity of 0.77.
The 10 protein features “represent a diverse array of pathways,” and the highest ranked feature was the serine protease prothrombin, which is a precursor to thrombin, the authors noted. “Multiple lines of evidence support that cerebrovascular disease may play a role in AD and that amyloid-beta may be involved in thrombosis, fibrinolysis, and inflammation via its interaction with the coagulation cascade,” the researchers wrote.
Two of the biomarkers – amyloid-beta A4 protein and NfL – have been examined in prior research and had a greater effect size in a secondary analysis that included participants with mild cognitive impairment and Alzheimer’s disease. This finding confirms “their connection with the more established disease state,” Dr. Ashton and colleagues said. In the secondary analysis, the optimal classifier included one demographic factor (APOE4 count) and nine protein features, eight of which also were used in the cognitively unimpaired classifier.
The study was funded in part by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, and many authors reported additional research support from various institutions. One author is an employee of Johnson & Johnson and a named inventor on unrelated biomarker intellectual property owned by Proteome Science and King’s College London.
SOURCE: Ashton NJ et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aau7220.
FROM SCIENCE ADVANCES
Key clinical point: Blood-based measures that predict amyloid-beta burden in preclinical Alzheimer’s disease have the potential to help investigators conduct clinical trials and aid in diagnostic management.
Major finding: A classifier developed using plasma proteomic analysis achieved an area under the receiver operator characteristic curve of 0.891.
Study details: An analysis of data from 238 cognitively unimpaired individuals from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH).
Disclosures: The study was funded in part by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, and many authors reported additional research support from various institutions. One author is an employee of Johnson & Johnson and a named inventor on unrelated biomarker intellectual property owned by Proteome Science and King’s College London.
Source: Ashton NJ et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aau7220.
Aerobic exercise may mitigate age-related cognitive decline
published in Neurology.
“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.
Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.
“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.
Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.
The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.
During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.
Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.
In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.
“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”
Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.
“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.
The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
published in Neurology.
“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.
Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.
“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.
Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.
The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.
During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.
Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.
In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.
“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”
Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.
“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.
The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
published in Neurology.
“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.
Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.
“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.
Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.
The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.
During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.
Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.
In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.
“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”
Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.
“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.
The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
FROM NEUROLOGY
Key clinical point: Among adults with below-average fitness, a 6-month aerobic exercise program significantly improves executive function.
Major finding: The effect is more pronounced as age increases.
Study details: A randomized, parallel-group, observer-masked, community-based clinical trial of 132 cognitively normal adults aged 20-67 years.
Disclosures: The study was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulted with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. Another reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
Source: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.