User login
CLL, MBL had lower response rates to flu vaccination, compared with healthy adults
Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.
In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.
“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.
The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.
The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
Lower response rate
At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.
“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.
“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.
This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.
Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.
In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.
“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.
The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.
The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
Lower response rate
At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.
“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.
“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.
This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.
Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.
In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.
“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.
The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.
The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
Lower response rate
At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.
“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.
“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.
This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.
FROM VACCINE
FDA okays new CAR T-cell treatment for large B-cell lymphomas
The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.
The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).
The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.
The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.
The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%.
“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”
Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.
The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.
Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.
Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.
A postmarketing study to further evaluate the long-term safety will also be required.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.
The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).
The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.
The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.
The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%.
“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”
Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.
The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.
Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.
Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.
A postmarketing study to further evaluate the long-term safety will also be required.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved lisocabtagene maraleucel (Breyanzi), a chimeric antigen receptor (CAR) T-cell product for the treatment of adults with certain types of relapsed or refractory large B-cell lymphoma who relapse or fail to respond to at least two systemic treatments.
The new approval comes with a risk evaluation and mitigation strategy (REMS) because of the risk for serious adverse events, including cytokine release syndrome (CRS).
The product, from Juno Therapeutics, a Bristol Myers Squibb company, is the third gene therapy to receive FDA approval for non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common type of non-Hodgkin lymphoma in adults, accounting for about a third of the approximately 77,000 cases diagnosed each year in the United States.
The FDA previously granted Breyanzi orphan drug, regenerative medicine advanced therapy (RMAT), and breakthrough therapy designations. The product is the first therapy with an RMAT designation to be licensed by the agency.
The new approval is based on efficacy and safety demonstrated in a pivotal phase 1 trial of more than 250 adults with relapsed or refractory large B-cell lymphoma. The complete remission rate after treatment with Breyanzi was 54%.
“Treatment with Breyanzi has the potential to cause severe side effects. The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities,” the FDA explained. “Both CRS and neurological events can be life-threatening.”
Other side effects, which typically present within 1-2 weeks after treatment, include hypersensitivity reactions, serious infections, low blood cell counts, and a weakened immune system, but some side effects may occur later.
The REMS requires special certification for facilities that dispense the product and “specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Breyanzi,” the FDA noted.
Breyanzi is not indicated for patients with primary central nervous system lymphoma, the FDA noted.
Facility certification involves training to recognize and manage the risks of CRS and neurologic toxicities.
A postmarketing study to further evaluate the long-term safety will also be required.
A version of this article first appeared on Medscape.com.
MS bears no effect on certain pregnancy complications, stillbirth, or congenital deformation
, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.
“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”
MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
Assessing pregnancy outcomes
This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.
Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.
“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
Comprehensive data
Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.
A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.
Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.
, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.
“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”
MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
Assessing pregnancy outcomes
This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.
Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.
“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
Comprehensive data
Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.
A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.
Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.
, according to a new study published online Feb. 3 in Neurology Clinical Practice. While pregnancy and childbirth are not regarded as conditions that engender high-risk pregnancy in the MS population, previous studies evaluating the effects of MS on pregnancy and parturition have yet to fully elucidate some outcomes for pregnant women and their babies in multiple sclerosis.
“Women with multiple sclerosis may be understandably concerned about the risk of pregnancy,” said Melinda Magyari, MD, PhD, a consultant at the University of Copenhagen. “While previous research has shown there is no higher risk of birth defect for babies born to women with MS, we wanted to find out if women with MS are at risk for a variety of pregnancy complications.”
MS is regarded as a progressive, neurological disease mediated by the immune system that demands careful consideration of numerous situations and life changes including family planning. The MS population is overwhelmingly female, as women account for three out of every four cases of MS. The majority of these women range from 20 to 40 years of age at the time of being diagnosed with MS. Despite the unknown risks of pregnancy-related complications and various perinatal complications in this patient population, women who have MS are not discouraged from conceiving.
Assessing pregnancy outcomes
This nationwide, population-based, cross-sectional study evaluated the pregnancies of 2,930 women with MS between Jan. 1, 1997, and Dec. 31, 2016, registered in the Danish Multiple Sclerosis Registry. The researchers compared pregnancy-related and prenatal outcomes to a 5% random sample of 56,958 randomly-selected pregnant women from Denmark’s general population who did not have MS. They found no differences in the risks associated with several pregnancy-related complications (e.g., preeclampsia, gestational diabetes, or placental complications), emergency Cesarean section (C-section), instrumental delivery, stillbirth, preterm birth, or congenital malformation. Apgar scores were low in both groups. A composite of various biometrics in newborns such as reflexes, muscle tone, and heart rate immediately following birth, the Apgar score is used to help assess the neonatal health, with a value of less than 7 considered low. Here, preterm birth is defined as delivery occurring before 37 weeks of gestation, and stillbirth describes a fetus born dead after 22 weeks of gestation.
Women in the MS cohort were more likely to have elective C-sections (odds ratio, 2.89 [95% confidence interval, 1.65-2.16]), induced labor (OR, 1.15 [95%CI, 1.01-1.31]) and have babies with low birth weight based on their gestational age (OR, 1.29 [95% CI, 1.04-1.60]). Nearly 30% of babies born in the cohort (n = 851) were born to mothers who had received disease-modifying therapy (DMT). Neonates exposed to DMT weighed an average of 116 g less than babies born to mothers who had not received DMT (3,378 g vs. 3,494 g) with a slightly lower gestational age (39 weeks as opposed to 40 weeks). However, babies born to mothers with MS were less likely to show signs of asphyxia (OR, 0.87 [95% CI, 0.78-0.97]) than the comparison cohort.
“We found overall, their pregnancies were just as healthy as those of the moms without MS,” Dr. Magyari said.
Comprehensive data
Denmark’s health care system has two key features that make it an attractive setting in which to conduct such a study – the first being its universal health care. The second advantage is that the country enacted several health registries in the 1970s and 1980s that enable the collection of more comprehensive data. For example, the Danish National Patient Register is a population-based registry that spans the entire nation, facilitating epidemiological research with what the study’s authors describe as “high generalizability.” Providing additional insights regarding the patient story helps add context to pregnancy and outcomes. Among the data collected on the women studied were demographics, contact information, and abortions, both spontaneous and medically induced. The country uses other databases and registries to capture additional data. For example, the Register of Legally Induced Abortions provides data regarding the context of medically induced abortions. In contrast, the Danish Medical Birth Registry provides context regarding specified variables regarding women’s pregnancies, delivery, and perinatal outcomes. Finally, the population’s education register offers information regarding patients’ educational history.
A key strength of this study is that the long duration of follow-up data from the Danish Medical Birth Registry, along with its comprehensive data collection, eliminates recall bias. Universal access to health care also improves the generalizability of data. A limitation of the study is its lack of data on maternal smoking and its effects on low gestational weights. The study also has some data gaps, including body mass index information missing from a large portion of the cohort. Finally, the sample size of newborns born to mothers who had received DMT therapy within the last 6 months of gestation was too underpowered to stratify based on first on first-line or second-line treatment.
Dr. Magyari served on scientific advisory boards for Biogen, Sanofi, Teva, Roche, Novartis, and Merck. She has also received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. Coauthors disclosed various fees received from Merck, Novartis, Biogen, Roche, Sanofi Genzyme, and Teva.
FROM NEUROLOGY CLINICAL PRACTICE
FDA approves intramuscular administration for peginterferon beta-1a in MS
“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.
Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.
Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.
The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.
Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.
The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.
The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.
A version of this article first appeared on Medscape.com.
“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.
Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.
Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.
The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.
Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.
The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.
The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.
A version of this article first appeared on Medscape.com.
“The new IM administration offers people living with relapsing MS the well-characterized efficacy and safety of Plegridy with the potential for significantly reduced injection site reactions,” Biogen said in a news release announcing the FDA action.
Plegridy is a pegylated version of interferon beta-1a, which prolongs the circulation time of the molecule in the body by increasing its size. The process extends the drug’s half-life, allowing for a less-frequent dosing schedule.
Peginterferon beta-1a administered subcutaneously was first approved by the FDA in 2014 based on data showing it significantly reduces MS relapses, disability progression, and brain lesions.
The FDA approved IM administration for peginterferon beta-1a based on data evaluating bioequivalence and adverse reactions associated with IM administration compared with subcutaneous (SC) administration in healthy volunteers.
Bioequivalence of the IM and SC dosing regimens was confirmed and volunteers receiving the drug through IM administration experienced fewer injection site reactions relative to those receiving SC administration (14.4% vs. 32.1%), the company said.
The overall safety profiles of IM and SC administration were generally similar, with no new safety signals.
The European Commission allowed marketing authorization for IM administration of peginterferon beta-1a in December 2020.
A version of this article first appeared on Medscape.com.
Cognitive effects seen as transient for Alzheimer’s drug atabecestat
according to follow-up results from a truncated clinical trial.
A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.
A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.
In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.
Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.
Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
Questions surround BACE inhibitors
Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.
Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.
While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue.
“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
Research should continue
Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.
“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”
Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.
“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.
Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.
according to follow-up results from a truncated clinical trial.
A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.
A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.
In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.
Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.
Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
Questions surround BACE inhibitors
Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.
Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.
While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue.
“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
Research should continue
Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.
“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”
Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.
“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.
Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.
according to follow-up results from a truncated clinical trial.
A blinded, placebo-controlled, manufacturer-sponsored trial that had randomized 557 patients with preclinical Alzheimer’s disease to 25 mg daily oral atabecestat, 5 mg atabecestat, or placebo, was halted in 2018 over concerns about liver toxicity. The main outcome measure of the trial was change on the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite, while two other scales were used to assess cognitive function and neuropsychological status.
A preliminary analysis found the higher dose of the atabecestat to significantly worsen subjects’ cognition starting at around 3 months of treatment, compared with placebo. Treatment with atabecestat was also seen associated with higher incidence of neuropsychiatric adverse events, including anxiety and depression.
In their follow-up study published Jan. 19, 2021 in JAMA Neurology (doi: 10.1001/jamaneurol.2020.4857), Reisa Sperling, MD, of Brigham and Women’s Hospital, Boston, and colleagues reported that the cognitive worsening and neuropsychiatric adverse effects seen linked to atabecestat treatment reverted to baseline levels within 6 months of halting treatment. Most of the worsening seen in the study was associated with episodic memory tasks, including “list learning, story memory, list recognition, story recall, and figure recall,” Dr. Sperling and colleagues found.
Atabecestat was also associated with “dose-related and duration-related decreases in whole-brain volume, compared with placebo treatment,” the investigators reported. Brain volume loss has been seen in trials of other beta-secretase (BACE) inhibitors and shown with one, umibecestat, to be reversible after stopping treatment.
Dr. Sperling and colleagues acknowledged as a major limitation of their study that just over a third of the cohort received another cognitive composite score after baseline. “The observation that cognitive worsening and neuropsychiatric-related [adverse events] recovered following discontinuation of atabecestat is encouraging but needs replication, given that the observation period after stopping treatment was variable and not preplanned,” the investigators wrote in their analysis. After a median exposure of 21 weeks to the study drug or placebo, subjects were followed off treatment for a median 15 weeks.
Questions surround BACE inhibitors
Development of atabecestat has been discontinued along with others in its class of agents, known as BACE inhibitors, which target an enzyme that initiates production of amyloid-beta, the plaque-forming peptide that is considered a driver of Alzheimer’s disease. In the past few years a number of BACE inhibitors have been shown in trials to worsen cognition in a dose-dependent way, compared with placebo. The reasons for these effects are still unknown.
Dr. Sperling and colleagues concluded that, if BACE investigators like atabecestat are to be studied anew, it must be at low doses, with more modest enzyme inhibition, and alongside careful safety and cognitive monitoring.
While no BACE inhibitor is currently in the pipeline for Alzheimer’s – trials of these agents have been stopped for futility or toxicity –Paul Aisen, MD of the University of Southern California, Los Angeles, and a coauthor of Dr. Sperling and colleagues’ study, commented that it was important that clinical investigation of BACE inhibitors continue.
“This drug class is optimal to correct the metabolic dysregulation that is likely a primary root cause” of Alzheimer’s disease, Dr. Aisen said in an interview. “Evidence from trials such as this suggest that the cognitive toxicity of BACE inhibitors is dose related, nonprogressive, and reversible. We should now focus on establishing the safety of relatively low-dose BACE inhibition so that such regimens can be tested in AD trials.”
Research should continue
Robert Vassar, PhD, of Northwestern University, Chicago, who was not a coauthor on the study, also expressed a desire for BACE inhibitor research to continue.
“It is my view that the cognitive worsening of atabecestat and the other BACE inhibitors was caused by overinhibition of the enzyme related to functions of certain BACE substrates in the brain,” Dr. Vassar commented. “A major question is whether a lower dose of BACE inhibitor – achieving about 30% inhibition – could be safe and lower amyloid-beta enough to delay onset in people still without symptoms. The good news of this study is that the atabecestat-related cognitive worsening is reversible, leaving open the possibility of low-dose prevention trials.”
Dr. Vassar noted that, with both doses of atabecestat, Dr. Sperling and colleagues did not see changes in neurofilament light or total tau, two biomarkers of neurodegeneration, but did report decreases in phosphorylated tau (p181 tau), a marker of disease progression, compared with placebo.
“This indicates that atabecestat did not cause neurodegeneration and in fact moved p181 tau in the beneficial direction for Alzheimer’s disease. Perhaps if it were not for the liver toxicity, the trial may have been completed and other Alzheimer’s disease biomarkers may have changed in the beneficial direction as well,” Dr. Vassar said.
Dr. Sperling and colleagues’ study was sponsored by Janssen, the manufacturer of atabecestat. Dr. Sperling disclosed receiving research funding from Janssen and other drug makers, while nearly all the study’s coauthors reported being directly employed by the sponsor or receiving industry funding. Dr. Aisen disclosed personal fees from several manufacturers and past fees from the sponsor. Dr. Vassar disclosed consulting and other financial relationships with biotechnology companies that did not include this study’s sponsor.
FROM JAMA NEUROLOGY
Is the EDSS an adequate outcome measure in secondary progressive MS trials?
Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from
For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
Comparing three outcome measures
The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.
Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.
The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
‘Considerable implications’ for the design of future clinical trials
In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”
The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.
Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.
Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from
For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
Comparing three outcome measures
The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.
Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.
The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
‘Considerable implications’ for the design of future clinical trials
In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”
The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.
Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.
Clinical trials enrolling patients with progressive multiple sclerosis (MS) commonly use the Expanded Disability Status Scale (EDSS), an instrument that looks at impairment across several different functional domains, as a primary outcome measure. But results from
For their research, published in the Jan. 5 issue of Neurology, Marcus W. Koch, MD, PhD, of the department of neurosciences at Hotchkiss Brain Institute at the University of Calgary (Alta.) and colleagues looked at data from the placebo arms of two randomized trials that collectively enrolled nearly 700 patients with secondary progressive MS (SPMS). The trials were similar in terms of baseline patient characteristics and level of disability.
Comparing three outcome measures
The investigators compared disability progression and improvement across each of the three instruments and their combinations. Because improvement is understood to occur only rarely in untreated secondary progressive MS, most improvement picked up in the placebo arm of a trial is assumed to be noise from random variation or measurement error.
Dr. Koch and colleagues found that the EDSS showed higher rates of improvement than the other tests. The EDSS also showed the smallest differences between progression and improvement among the three instruments, with improvement rate over time increasing in parallel with disability progression rates. With the other two tests, improvement rates remained low – at 10% or less – while disability was seen steadily increasing over time.
The results, the investigators wrote in their analysis, suggest that the timed 25-foot walk and 9-hole peg test are the more reliable outcome measures. The reason “may simply lie in the fact that both the timed 25-foot walk and 9-hole peg test are objective and quantitative interval-scaled measures while the EDSS is a graded categorical measure.” As primary outcome measures in clinical trials, “the lower noise of the timed 25-foot walk and 9-hole peg test may make them preferable over the EDSS,” Dr. Koch and colleagues concluded. The investigators noted that a 2019 analysis of different MS disability scales across more than 13,000 patients in 14 trials did not find such stark differences – but that the patients in the pooled trials had less disability at baseline (median EDSS score of 2.5, compared with 6.0 for the two trials in Dr. Koch and colleagues’ study). This suggests, the investigators wrote, “that the timed 25-foot walk and 9-hole peg test may be more useful outcomes in patients with a progressive disease course and with greater baseline disability.”
‘Considerable implications’ for the design of future clinical trials
In an accompanying editorial, Tomas Kalincik, MD, PhD, of the University of Melbourne, along with colleagues in Italy and Britain, praised Dr. Koch and colleagues’ study as having “considerable implications for the design of future clinical trials because detecting a treatment effect on an outcome that is subject to large measurement error is difficult.” Most trials in progressive MS use change in EDSS score as their primary or key secondary outcomes. “However, as the authors elegantly show, other, more reliable clinical outcomes are needed. As we are revisiting our biological hypotheses for treatment of progressive MS, perhaps the time has come that we should also revisit the instruments that we use to examine their efficacy.”
The editorialists allowed for the possibility that something besides noise or measurement error could be responsible for the disparities seen across the instruments. “An alternative interpretation of the presented results could be that recovery of neurologic function is more common in SPMS than what we had previously thought and that EDSS is more sensitive to its detection than the other two measures,” they wrote.
Dr. Koch and colleagues’ study received no outside funding. Dr. Koch disclosed consulting fees and other financial support from several drug manufacturers, and three coauthors also disclosed financial relationships with pharmaceutical companies. All three editorial writers disclosed similar relationships.
FROM NEUROLOGY
Idiopathic intracranial hypertension is on the rise
corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).
The study was published online Jan. 20 in Neurology.
IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.
People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.
Population study in Wales
Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.
For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.
“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”
Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
Reasons for the increase
“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”
The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.
“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.
IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.
The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.
“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.
They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.
They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.
In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.
“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.
The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).
The study was published online Jan. 20 in Neurology.
IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.
People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.
Population study in Wales
Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.
For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.
“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”
Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
Reasons for the increase
“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”
The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.
“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.
IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.
The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.
“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.
They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.
They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.
In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.
“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.
The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
corresponding to population increases in body mass index (BMI), a new study has shown. “The condition is associated with a high rate of health care utilization, so the increasing incidence has important implications for health care professionals and policy makers in addressing the associated comorbidities,” said senior author William Owen Pickrell, PhD, Swansea University (Wales).
The study was published online Jan. 20 in Neurology.
IIH is a condition of unknown etiology that is strongly associated with obesity, the researchers noted. Predominantly affecting women of childbearing age, it causes chronic disabling headaches, visual disturbance, and in a minority of patients, permanent visual loss. The definitive management is weight loss, but a minority of patients require surgery to preserve vision.
People with IIH potentially have high rates of health care utilization, multiple specialist consultations, diagnostic tests, CSF diversion procedures, and complications related to CSF diversion surgery.
Population study in Wales
Given that there is a paucity of data regarding the epidemiology, health care utilization, and outcomes of people with IIH, Dr. Pickrell and colleagues conducted the current retrospective cohort study, which aimed to determine the temporal trends of IIH incidence and prevalence in Wales and health care utilization associated with IIH. They also investigated the effects of socioeconomic deprivation and obesity on IIH epidemiology.
For the study, they used and validated primary and secondary care IIH diagnostic codes within the Secure Anonymised Information Linkage data bank, which is part of the national e-health records research infrastructure for Wales, to ascertain IIH cases and controls between 2003 and 2017. In total, 35 million patient-years of data were analyzed. Information was recorded on body mass index, deprivation quintile, CSF diversion surgery, and unscheduled hospital admissions in case and control cohorts.
“This is the first time the diagnostic codes for this condition have been validated. This is important as it is critical if we are studying a condition to know that the individuals we are studying actually have that condition,” Dr. Pickrell commented. “We were able to establish that the diagnostic codes were 92% sensitive and 87% specific – that’s pretty good.”
Results showed a significant increase in IIH incidence and prevalence in Wales. The prevalence of IIH in Wales increased sixfold from 12/100,000 in 2003 to 76/100,000 in 2017, and the incidence of IIH increased threefold from 2.3/100,000 per year in 2003 to 7.8/100,000 per year in 2017. This corresponded with increases in obesity rates: 29% of the population was obese in 2003, compared with 40% in 2017.
Reasons for the increase
“The considerable increase in IIH incidence is multifactorial but likely predominately due to rising obesity rates,” the authors noted. “The worldwide prevalence of obesity nearly tripled between 1975 and 2016 and therefore these results also have global relevance.”
The increase in IIH incidence may also be attributable to increased IIH diagnosis rates because of raised awareness of the condition and greater use of digital fundoscopy at routine optometry appointments, they suggested.
“We found a strong association between increasing BMI, sex (being female), and IIH. Around 85% of our IIH cohort were female, similar to other studies, and we also found a significant association with increased deprivation and IIH, particularly in women,” the authors reported.
IIH is associated with increasing deprivation in women even after adjusting for obesity suggesting additional etiologic factors associated with deprivation apart from BMI; this effect was not seen in men, pointing to sex-specific drivers for IIH, they added.
The results also show that individuals with IIH have increased rates of unscheduled health care utilization compared with a matched-control cohort. The rate ratio for unscheduled hospital admissions in the IIH cohort, compared with controls was 5.28.
“A considerable proportion of this excess in unscheduled hospital admissions occurs at the time of diagnosis and can be explained by the need for urgent investigation of papilloedema with brain imaging and spinal fluid analysis. However, there is also a considerable excess in unscheduled hospital admissions up to 2 years after diagnosis,” the authors reported.
They suggested that these admissions are likely to be for severe headache, and they say there is some scope to reduce emergency admissions through better management of headache, patient education, and rapid access to outpatient specialist advice.
They also pointed out that the rate of unscheduled admissions is higher in the IIH cohort in the 3 years leading up to diagnosis, suggesting an opportunity for earlier diagnosis and earlier intervention.
In their study population, 8% of patients with IIH received CSF diversion procedures a mean of 1.3 years after diagnosis, and these patients showed significantly increased unscheduled health care admission rates, compared with IIH patients who had not undergone such procedures.
“There are frequent complications with the shunts after surgery, which causes a high revision rate,” Dr. Pickrell commented. In this study, 40% of patients undergoing CSF diversion needed at least one CSF shunt revision procedure.
The study was supported by the Brain Repair and Intracranial Neurotherapeutics unit, Wales Gene Park, Health Data Research UK, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Wales), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Stem cell transplant shows long-term benefit in MS
The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.
Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.
“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”
The study was published online Jan. 20 in Neurology.
“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.
The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.
“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
Renewing the immune system
The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.
“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”
Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.
Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.
For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.
Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.
Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.
Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.
However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.
In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.
“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
Potent and durable efficacy, with caveats
Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”
The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”
He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”
To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.
The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.
Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.
“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”
The study was published online Jan. 20 in Neurology.
“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.
The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.
“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
Renewing the immune system
The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.
“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”
Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.
Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.
For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.
Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.
Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.
Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.
However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.
In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.
“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
Potent and durable efficacy, with caveats
Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”
The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”
He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”
To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.
The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The benefits of autologous hematopoietic stem cell transplant (AHSCT) for patients with multiple sclerosis (MS) persist for more than 10 years in the majority of patents, new data show. The study reports on 210 Italian patients who underwent AHSCT between 2007 and 2019. Among the entire study cohort, 79.5% of patients had not experienced worsening of disability at 5 years, and 65.5% had not experienced it at 10 years.
Patients with relapsing remitting MS had better results, with 85.5% experiencing no worsening of disability at 5 years, and 71.3% at 10 years. Among patients with progressive MS, 71.0% showed no worsening of disability at 5 years, and 57.2% at 10 years.
“This is the longest follow-up of AHSCT in MS patients so far to be reported,” said study author Matilde Inglese, MD, University of Genoa (Italy). “We have shown AHSCT to be highly effective to prevent long-term disability worsening in most treated patients.”
The study was published online Jan. 20 in Neurology.
“We suggest that AHSCT should be considered as a treatment strategy for MS not responding to conventional therapy,” the authors concluded.
The study had no control group, so a direct comparison is not possible. Nevertheless, Dr. Inglese said she believed these results are better than those that would be achieved with disease-modifying drug therapy for similar patients.
“The best patient candidates for this procedure are those with highly active multiple sclerosis who are not responsive to high-efficacy drugs, such as alemtuzumab or ocrelizumab,” Dr. Inglese commented. “Younger patients with an aggressive form of relapsing remitting MS tend to do the best, although patients with progressive forms of MS who still have active lesions on MRI also benefit.”
Renewing the immune system
The transplant procedure involves giving high-dose cyclophosphamide to stimulate mobilization of bone marrow stem cells, which are collected from peripheral blood. Patients then undergo intense immunosuppression with a cocktail of drugs to remove the autoreactive T cells, and the stem cells, which are not autoreactive, are reinfused.
“We are effectively renewing the immune system,” Dr. Inglese said. “While it is not correct to call it a cure, as we are not eliminating the etiology of the disease, it is the closest to complete suppression of the disease that we can get.”
Other results from the study show that among patients with relapsing remitting MS, rates of relapse-free survival were 78.1% at 5 years and 63.5% at 10 years.
Better results were achieved for patients who received the BEAM+ATG conditioning regimen for immunosuppression. That regimen includes carmustine, cytosine-arabinoside, etoposide, and melphalan, followed by rabbit antithymocyte globulin. Among patients with relapsing remitting disease who were treated with this protocol, rates of relapse-free survival were 86.4% at 5 years and 77.0% at 10 years.
For patients with relapsing remitting MS, the probability of achieving NEDA-3 status (no evidence of disease activity, including the absence of clinical relapses, disability worsening, and MRI inflammatory activity) was 62.2% at 5 years and 40.5% at 10 years.
Among those patients with relapsing remitting MS who received the BEAM+ATG conditioning protocol, NEDA-3 status was achieved in 67.7% at 5 years and in 54.9% at 10 years.
Three deaths occurred within 100 days following AHSCT (1.4% of the entire study population). One patient developed pulmonary thromboembolism, received fibrinolytic treatment, and died 48 hours later after intracranial hemorrhage. The second patient experienced engraftment failure and died 24 days after transplant because of an opportunistic infection. The third patient died 1 month after transplant from Wernicke-like encephalopathy. All the patients who died received the BEAM+ATG conditioning regimen. No transplant-related deaths occurred in patients who underwent transplant after 2007.
Dr. Inglese noted that the mortality rate associated with AHSCT has been greatly reduced in recent years. “We are seeing a very low mortality rate – about 0.3% – thanks to improvements in the procedure and better patient selection. This seems acceptable, given that we are treating patients with very aggressive disease who have a high risk of becoming significantly disabled relatively early in life,” she commented.
However, it is vitally important that the procedure be conducted in a specialized center with a highly experienced multidisciplinary team, she stressed.
In the Neurology article, the authors concluded: “Although patients with RRMS [relapsing remitting MS] are those who benefit the most from transplant, AHSCT has been also shown to prevent disability worsening in a large proportion of patients with active progressive MS.
“The BEAM+ATG conditioning protocol, although associated with a higher transplant mortality rate, was associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity, allowing complete disease control in a higher proportion of patients,” they wrote.
Potent and durable efficacy, with caveats
Commenting on these latest findings, Jeffrey A. Cohen, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, said: “AHSCT appears to have potent and durable efficacy in MS but is associated with significant risk and cost.”
The patients who are most likely to benefit are young and have experienced the onset of disease relatively recently. They are still ambulatory with highly active MS and have experienced recent clinical relapses and/or MRI lesion activity, and such activity continues despite disease-modifying therapy, Dr. Cohen noted. He added that “AHSCT is a reasonable option for such patients who have essentially failed the available disease-modifying therapy options.”
He pointed out that the key question is where AHSCT belongs in the overall MS algorithm relative to other high-efficacy therapies. “We need to know whether it should be used more broadly rather than as a last resort.”
To address that question, several randomized trials comparing AHSCT with high-efficacy disease-modifying therapy are in progress, including the National Institutes of Health–sponsored BEAT-MS trial in the United States (for which Dr. Cohen is the lead investigator) and four European trials – NET-MS (for which Dr. Inglese is the lead investigator), STAR-MS, RAM-MS, and COAST-MS.
The current study was partially funded and supported by the Italian Multiple Sclerosis Foundation. Dr. Inglese disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Blood biomarker may predict Alzheimer’s disease progression
new research suggests.
In a study of more than 1,000 participants, changes over time in levels of p-tau181 were associated with prospective neurodegeneration and cognitive decline characteristic of Alzheimer’s disease. These results have implications for investigative trials as well as clinical practice, the investigators noted.
Like p-tau181, neurofilament light chain (NfL) is associated with imaging markers of degeneration and cognitive decline; in contrast to the findings related to p-tau181, however, the associations between NfL and these outcomes are not specific to Alzheimer’s disease. Using both biomarkers could improve prediction of outcomes and patient monitoring, according to the researchers.
“These findings demonstrate that p-tau181 and NfL in blood have individual and complementary potential roles in the diagnosis and the monitoring of neurodegenerative disease,” said coinvestigator Michael Schöll, PhD, senior lecturer in psychiatry and neurochemistry at the University of Gothenburg (Sweden).
“With the reservation that we did not assess domain-specific cognitive impairment, p-tau181 was also more strongly associated with cognitive decline than was NfL,” Dr. Schöll added.
The findings were published online Jan. 11 in JAMA Neurology.
Biomarker-tracked neurodegeneration
Monitoring a patient’s neurodegenerative changes is important for tracking Alzheimer’s disease progression. Although clinicians can detect amyloid-beta and tau pathology using PET and cerebrospinal fluid (CSF) biomarkers, the widespread use of the latter has been hampered by cost and limited availability of necessary equipment. The use of blood-based biomarkers is not limited in these ways, and so they could aid in diagnosis and patient monitoring.
Previous studies have suggested that p-tau181 is a marker of Alzheimer’s disease status.
In the current study, investigators examined whether baseline and longitudinal levels of p-tau181 in plasma were associated with progressive neurodegeneration related to the disease. They analyzed data from the Alzheimer’s Disease Neuroimaging Initiative, a multicenter study designed to identify biomarkers for the detection and tracking of Alzheimer’s disease.
The researchers selected data for cognitively unimpaired and cognitively impaired participants who participated in the initiative between Feb. 1, 2007, and June 6, 2016. Participants were eligible for inclusion if plasma p-tau181 and NfL data were available for them and if they had undergone at least one 18fluorodeoxyglucose (FDG)–PET scan or structural T1 MRI at the same study visit. Most had also undergone imaging with 18florbetapir, which detects amyloid-beta.
A single-molecule array was used to analyze concentrations of p-tau181 and NfL in participants’ blood samples. Outliers for p-tau181 and NfL concentrations were excluded from further analysis. Using participants’ FDG-PET scans, the investigators measured glucose hypometabolism characteristic of Alzheimer’s disease. They used T1-weighted MRI scans to measure gray-matter volume.
Cognitively unimpaired participants responded to the Preclinical Alzheimer Cognitive Composite, a measure designed to detect early cognitive changes in cognitively normal patients with Alzheimer’s disease pathology. Cognitively impaired participants underwent the Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks to assess the severity of cognitive impairment.
The researchers included 1,113 participants (54% men; 89% non-Hispanic Whites; mean age, 74 years) in their analysis. In all, 378 participants were cognitively unimpaired, and 735 were cognitively impaired. Of the latter group, 73% had mild cognitive impairment, and 27% had Alzheimer’s disease dementia.
Atrophy predictor
Results showed that higher plasma p-tau181 levels at baseline were associated with more rapid progression of hypometabolism and atrophy in areas vulnerable to Alzheimer’s disease among cognitively impaired participants (FDG-PET standardized uptake value ratio change, r = –0.28; P < .001; gray-matter volume change, r = –0.28; P < .001).
The association with atrophy progression in cognitively impaired participants was stronger for p-tau181 than for NfL.
Plasma p-tau181 levels at baseline also predicted atrophy in temporoparietal regions vulnerable to Alzheimer’s disease among cognitively unimpaired participants (r = –0.11; P = .03). NfL, however, was associated with progressive atrophy in frontal regions among cognitively unimpaired participants.
At baseline, plasma p-tau181 levels were associated with prospective cognitive decline in both the cognitively unimpaired group (r = −0.12; P = .04) and the cognitively impaired group (r = 0.35; P < .001). However, plasma NfL was linked to cognitive decline only among those who were cognitively impaired (r = 0.26; P < .001).
Additional analyses showed that p-tau181, unlike NfL, was associated with hypometabolism and atrophy only in participants with amyloid-beta, regardless of cognitive status.
Between 25% and 45% of the association between baseline p-tau181 level and cognitive decline was mediated by baseline imaging markers of neurodegeneration. This finding suggests that another factor, such as regional tau pathology, might have an independent and direct effect on cognition, Dr. Schöll noted.
Furthermore, changes over time in p-tau181 levels were associated with cognitive decline in the cognitively unimpaired (r = –0.24; P < .001) and cognitively impaired (r = 0.34; P < .001) participants. Longitudinal changes in this biomarker also were associated with a prospective decrease in glucose metabolism in cognitively unimpaired (r = –0.05; P = .48) and cognitively impaired (r = –0.27; P < .001) participants, but the association was only significant in the latter group.
Changes over time in p-tau181 levels were linked to prospective decreases in gray-matter volume in brain regions highly characteristic of Alzheimer’s disease in those who were cognitively unimpaired (r = –0.19; P < .001) and those who were cognitively impaired (r = –0.31, P < .001). However, these associations were obtained only in patients with amyloid-beta.
Dr. Schöll noted that blood-based biomarkers that are sensitive to Alzheimer’s disease could greatly expand patients’ access to a diagnostic workup and could improve screening for clinical trials.
“While the final validation of the existence and the monitoring of potential changes of neuropathology in vivo is likely to be conducted using neuroimaging modalities such as PET, our results suggest that at least a part of these examinations could be replaced by regular blood tests,” Dr. Schöll said.
Lead author Alexis Moscoso, PhD, a postdoctoral researcher in psychiatry and neurochemistry at the University of Gothenburg, reported that the researchers will continue validating blood-based biomarkers, especially against established and well-validated neuroimaging methods. “We are also hoping to be able to compare existing and novel blood-based Alzheimer’s disease biomarkers head to head to establish the individual roles each of these play in the research and diagnosis of Alzheimer’s disease,” Dr. Moscoso said.
‘Outstanding study’
Commenting on the findings, David S. Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., said that this is “an outstanding study” because of its large number of participants and because the investigators are “world leaders in the technology of measuring plasma p-tau and NfL.”
Dr. Knopman, who was not involved with the research, noted that the study had no substantive weaknesses.
“The biggest advantages of a blood-based biomarker over CSF- and PET-based biomarkers of Alzheimer disease are the obvious ones of accessibility, cost, portability, and ease of repeatability,” he said.
“As CSF and PET exams are largely limited to major medical centers, valid blood-based biomarkers of Alzheimer disease that are reasonably specific make large-scale epidemiological studies that investigate dementia etiologies in rural or urban and diverse communities feasible,” he added.
Whereas p-tau181 appears to be specific for plaque and tangle disease, NfL is a nonspecific marker of neurodegeneration.
“Each has a role that could be valuable, depending on the circumstance,” said Dr. Knopman. “Plasma NfL has already proved itself useful in frontotemporal degeneration and chronic traumatic encephalopathy, for example.”
He noted that future studies should examine how closely p-tau181 and NfL align with more granular and direct measures of Alzheimer’s disease–related brain pathologies.
“There has got to be some loss of fidelity in detecting abnormality in going from brain tissue to blood, which might siphon off some time-related and severity-related information,” said Dr. Knopman.
“The exact role that plasma p-tau and NfL will play remains to be seen, because the diagnostic information that these biomarkers provide is contingent on the existence of interventions that require specific or nonspecific information about progressive neurodegeneration due to Alzheimer disease,” he added.
The study was funded by grants from the Spanish Instituto de Salud Carlos III, the Brightfocus Foundation, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. Dr. Schöll reported serving on a scientific advisory board for Servier on matters unrelated to this study. Dr. Moscoso and Dr. Knopman have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
In a study of more than 1,000 participants, changes over time in levels of p-tau181 were associated with prospective neurodegeneration and cognitive decline characteristic of Alzheimer’s disease. These results have implications for investigative trials as well as clinical practice, the investigators noted.
Like p-tau181, neurofilament light chain (NfL) is associated with imaging markers of degeneration and cognitive decline; in contrast to the findings related to p-tau181, however, the associations between NfL and these outcomes are not specific to Alzheimer’s disease. Using both biomarkers could improve prediction of outcomes and patient monitoring, according to the researchers.
“These findings demonstrate that p-tau181 and NfL in blood have individual and complementary potential roles in the diagnosis and the monitoring of neurodegenerative disease,” said coinvestigator Michael Schöll, PhD, senior lecturer in psychiatry and neurochemistry at the University of Gothenburg (Sweden).
“With the reservation that we did not assess domain-specific cognitive impairment, p-tau181 was also more strongly associated with cognitive decline than was NfL,” Dr. Schöll added.
The findings were published online Jan. 11 in JAMA Neurology.
Biomarker-tracked neurodegeneration
Monitoring a patient’s neurodegenerative changes is important for tracking Alzheimer’s disease progression. Although clinicians can detect amyloid-beta and tau pathology using PET and cerebrospinal fluid (CSF) biomarkers, the widespread use of the latter has been hampered by cost and limited availability of necessary equipment. The use of blood-based biomarkers is not limited in these ways, and so they could aid in diagnosis and patient monitoring.
Previous studies have suggested that p-tau181 is a marker of Alzheimer’s disease status.
In the current study, investigators examined whether baseline and longitudinal levels of p-tau181 in plasma were associated with progressive neurodegeneration related to the disease. They analyzed data from the Alzheimer’s Disease Neuroimaging Initiative, a multicenter study designed to identify biomarkers for the detection and tracking of Alzheimer’s disease.
The researchers selected data for cognitively unimpaired and cognitively impaired participants who participated in the initiative between Feb. 1, 2007, and June 6, 2016. Participants were eligible for inclusion if plasma p-tau181 and NfL data were available for them and if they had undergone at least one 18fluorodeoxyglucose (FDG)–PET scan or structural T1 MRI at the same study visit. Most had also undergone imaging with 18florbetapir, which detects amyloid-beta.
A single-molecule array was used to analyze concentrations of p-tau181 and NfL in participants’ blood samples. Outliers for p-tau181 and NfL concentrations were excluded from further analysis. Using participants’ FDG-PET scans, the investigators measured glucose hypometabolism characteristic of Alzheimer’s disease. They used T1-weighted MRI scans to measure gray-matter volume.
Cognitively unimpaired participants responded to the Preclinical Alzheimer Cognitive Composite, a measure designed to detect early cognitive changes in cognitively normal patients with Alzheimer’s disease pathology. Cognitively impaired participants underwent the Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks to assess the severity of cognitive impairment.
The researchers included 1,113 participants (54% men; 89% non-Hispanic Whites; mean age, 74 years) in their analysis. In all, 378 participants were cognitively unimpaired, and 735 were cognitively impaired. Of the latter group, 73% had mild cognitive impairment, and 27% had Alzheimer’s disease dementia.
Atrophy predictor
Results showed that higher plasma p-tau181 levels at baseline were associated with more rapid progression of hypometabolism and atrophy in areas vulnerable to Alzheimer’s disease among cognitively impaired participants (FDG-PET standardized uptake value ratio change, r = –0.28; P < .001; gray-matter volume change, r = –0.28; P < .001).
The association with atrophy progression in cognitively impaired participants was stronger for p-tau181 than for NfL.
Plasma p-tau181 levels at baseline also predicted atrophy in temporoparietal regions vulnerable to Alzheimer’s disease among cognitively unimpaired participants (r = –0.11; P = .03). NfL, however, was associated with progressive atrophy in frontal regions among cognitively unimpaired participants.
At baseline, plasma p-tau181 levels were associated with prospective cognitive decline in both the cognitively unimpaired group (r = −0.12; P = .04) and the cognitively impaired group (r = 0.35; P < .001). However, plasma NfL was linked to cognitive decline only among those who were cognitively impaired (r = 0.26; P < .001).
Additional analyses showed that p-tau181, unlike NfL, was associated with hypometabolism and atrophy only in participants with amyloid-beta, regardless of cognitive status.
Between 25% and 45% of the association between baseline p-tau181 level and cognitive decline was mediated by baseline imaging markers of neurodegeneration. This finding suggests that another factor, such as regional tau pathology, might have an independent and direct effect on cognition, Dr. Schöll noted.
Furthermore, changes over time in p-tau181 levels were associated with cognitive decline in the cognitively unimpaired (r = –0.24; P < .001) and cognitively impaired (r = 0.34; P < .001) participants. Longitudinal changes in this biomarker also were associated with a prospective decrease in glucose metabolism in cognitively unimpaired (r = –0.05; P = .48) and cognitively impaired (r = –0.27; P < .001) participants, but the association was only significant in the latter group.
Changes over time in p-tau181 levels were linked to prospective decreases in gray-matter volume in brain regions highly characteristic of Alzheimer’s disease in those who were cognitively unimpaired (r = –0.19; P < .001) and those who were cognitively impaired (r = –0.31, P < .001). However, these associations were obtained only in patients with amyloid-beta.
Dr. Schöll noted that blood-based biomarkers that are sensitive to Alzheimer’s disease could greatly expand patients’ access to a diagnostic workup and could improve screening for clinical trials.
“While the final validation of the existence and the monitoring of potential changes of neuropathology in vivo is likely to be conducted using neuroimaging modalities such as PET, our results suggest that at least a part of these examinations could be replaced by regular blood tests,” Dr. Schöll said.
Lead author Alexis Moscoso, PhD, a postdoctoral researcher in psychiatry and neurochemistry at the University of Gothenburg, reported that the researchers will continue validating blood-based biomarkers, especially against established and well-validated neuroimaging methods. “We are also hoping to be able to compare existing and novel blood-based Alzheimer’s disease biomarkers head to head to establish the individual roles each of these play in the research and diagnosis of Alzheimer’s disease,” Dr. Moscoso said.
‘Outstanding study’
Commenting on the findings, David S. Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., said that this is “an outstanding study” because of its large number of participants and because the investigators are “world leaders in the technology of measuring plasma p-tau and NfL.”
Dr. Knopman, who was not involved with the research, noted that the study had no substantive weaknesses.
“The biggest advantages of a blood-based biomarker over CSF- and PET-based biomarkers of Alzheimer disease are the obvious ones of accessibility, cost, portability, and ease of repeatability,” he said.
“As CSF and PET exams are largely limited to major medical centers, valid blood-based biomarkers of Alzheimer disease that are reasonably specific make large-scale epidemiological studies that investigate dementia etiologies in rural or urban and diverse communities feasible,” he added.
Whereas p-tau181 appears to be specific for plaque and tangle disease, NfL is a nonspecific marker of neurodegeneration.
“Each has a role that could be valuable, depending on the circumstance,” said Dr. Knopman. “Plasma NfL has already proved itself useful in frontotemporal degeneration and chronic traumatic encephalopathy, for example.”
He noted that future studies should examine how closely p-tau181 and NfL align with more granular and direct measures of Alzheimer’s disease–related brain pathologies.
“There has got to be some loss of fidelity in detecting abnormality in going from brain tissue to blood, which might siphon off some time-related and severity-related information,” said Dr. Knopman.
“The exact role that plasma p-tau and NfL will play remains to be seen, because the diagnostic information that these biomarkers provide is contingent on the existence of interventions that require specific or nonspecific information about progressive neurodegeneration due to Alzheimer disease,” he added.
The study was funded by grants from the Spanish Instituto de Salud Carlos III, the Brightfocus Foundation, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. Dr. Schöll reported serving on a scientific advisory board for Servier on matters unrelated to this study. Dr. Moscoso and Dr. Knopman have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
new research suggests.
In a study of more than 1,000 participants, changes over time in levels of p-tau181 were associated with prospective neurodegeneration and cognitive decline characteristic of Alzheimer’s disease. These results have implications for investigative trials as well as clinical practice, the investigators noted.
Like p-tau181, neurofilament light chain (NfL) is associated with imaging markers of degeneration and cognitive decline; in contrast to the findings related to p-tau181, however, the associations between NfL and these outcomes are not specific to Alzheimer’s disease. Using both biomarkers could improve prediction of outcomes and patient monitoring, according to the researchers.
“These findings demonstrate that p-tau181 and NfL in blood have individual and complementary potential roles in the diagnosis and the monitoring of neurodegenerative disease,” said coinvestigator Michael Schöll, PhD, senior lecturer in psychiatry and neurochemistry at the University of Gothenburg (Sweden).
“With the reservation that we did not assess domain-specific cognitive impairment, p-tau181 was also more strongly associated with cognitive decline than was NfL,” Dr. Schöll added.
The findings were published online Jan. 11 in JAMA Neurology.
Biomarker-tracked neurodegeneration
Monitoring a patient’s neurodegenerative changes is important for tracking Alzheimer’s disease progression. Although clinicians can detect amyloid-beta and tau pathology using PET and cerebrospinal fluid (CSF) biomarkers, the widespread use of the latter has been hampered by cost and limited availability of necessary equipment. The use of blood-based biomarkers is not limited in these ways, and so they could aid in diagnosis and patient monitoring.
Previous studies have suggested that p-tau181 is a marker of Alzheimer’s disease status.
In the current study, investigators examined whether baseline and longitudinal levels of p-tau181 in plasma were associated with progressive neurodegeneration related to the disease. They analyzed data from the Alzheimer’s Disease Neuroimaging Initiative, a multicenter study designed to identify biomarkers for the detection and tracking of Alzheimer’s disease.
The researchers selected data for cognitively unimpaired and cognitively impaired participants who participated in the initiative between Feb. 1, 2007, and June 6, 2016. Participants were eligible for inclusion if plasma p-tau181 and NfL data were available for them and if they had undergone at least one 18fluorodeoxyglucose (FDG)–PET scan or structural T1 MRI at the same study visit. Most had also undergone imaging with 18florbetapir, which detects amyloid-beta.
A single-molecule array was used to analyze concentrations of p-tau181 and NfL in participants’ blood samples. Outliers for p-tau181 and NfL concentrations were excluded from further analysis. Using participants’ FDG-PET scans, the investigators measured glucose hypometabolism characteristic of Alzheimer’s disease. They used T1-weighted MRI scans to measure gray-matter volume.
Cognitively unimpaired participants responded to the Preclinical Alzheimer Cognitive Composite, a measure designed to detect early cognitive changes in cognitively normal patients with Alzheimer’s disease pathology. Cognitively impaired participants underwent the Alzheimer Disease Assessment Scale–Cognitive Subscale with 13 tasks to assess the severity of cognitive impairment.
The researchers included 1,113 participants (54% men; 89% non-Hispanic Whites; mean age, 74 years) in their analysis. In all, 378 participants were cognitively unimpaired, and 735 were cognitively impaired. Of the latter group, 73% had mild cognitive impairment, and 27% had Alzheimer’s disease dementia.
Atrophy predictor
Results showed that higher plasma p-tau181 levels at baseline were associated with more rapid progression of hypometabolism and atrophy in areas vulnerable to Alzheimer’s disease among cognitively impaired participants (FDG-PET standardized uptake value ratio change, r = –0.28; P < .001; gray-matter volume change, r = –0.28; P < .001).
The association with atrophy progression in cognitively impaired participants was stronger for p-tau181 than for NfL.
Plasma p-tau181 levels at baseline also predicted atrophy in temporoparietal regions vulnerable to Alzheimer’s disease among cognitively unimpaired participants (r = –0.11; P = .03). NfL, however, was associated with progressive atrophy in frontal regions among cognitively unimpaired participants.
At baseline, plasma p-tau181 levels were associated with prospective cognitive decline in both the cognitively unimpaired group (r = −0.12; P = .04) and the cognitively impaired group (r = 0.35; P < .001). However, plasma NfL was linked to cognitive decline only among those who were cognitively impaired (r = 0.26; P < .001).
Additional analyses showed that p-tau181, unlike NfL, was associated with hypometabolism and atrophy only in participants with amyloid-beta, regardless of cognitive status.
Between 25% and 45% of the association between baseline p-tau181 level and cognitive decline was mediated by baseline imaging markers of neurodegeneration. This finding suggests that another factor, such as regional tau pathology, might have an independent and direct effect on cognition, Dr. Schöll noted.
Furthermore, changes over time in p-tau181 levels were associated with cognitive decline in the cognitively unimpaired (r = –0.24; P < .001) and cognitively impaired (r = 0.34; P < .001) participants. Longitudinal changes in this biomarker also were associated with a prospective decrease in glucose metabolism in cognitively unimpaired (r = –0.05; P = .48) and cognitively impaired (r = –0.27; P < .001) participants, but the association was only significant in the latter group.
Changes over time in p-tau181 levels were linked to prospective decreases in gray-matter volume in brain regions highly characteristic of Alzheimer’s disease in those who were cognitively unimpaired (r = –0.19; P < .001) and those who were cognitively impaired (r = –0.31, P < .001). However, these associations were obtained only in patients with amyloid-beta.
Dr. Schöll noted that blood-based biomarkers that are sensitive to Alzheimer’s disease could greatly expand patients’ access to a diagnostic workup and could improve screening for clinical trials.
“While the final validation of the existence and the monitoring of potential changes of neuropathology in vivo is likely to be conducted using neuroimaging modalities such as PET, our results suggest that at least a part of these examinations could be replaced by regular blood tests,” Dr. Schöll said.
Lead author Alexis Moscoso, PhD, a postdoctoral researcher in psychiatry and neurochemistry at the University of Gothenburg, reported that the researchers will continue validating blood-based biomarkers, especially against established and well-validated neuroimaging methods. “We are also hoping to be able to compare existing and novel blood-based Alzheimer’s disease biomarkers head to head to establish the individual roles each of these play in the research and diagnosis of Alzheimer’s disease,” Dr. Moscoso said.
‘Outstanding study’
Commenting on the findings, David S. Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., said that this is “an outstanding study” because of its large number of participants and because the investigators are “world leaders in the technology of measuring plasma p-tau and NfL.”
Dr. Knopman, who was not involved with the research, noted that the study had no substantive weaknesses.
“The biggest advantages of a blood-based biomarker over CSF- and PET-based biomarkers of Alzheimer disease are the obvious ones of accessibility, cost, portability, and ease of repeatability,” he said.
“As CSF and PET exams are largely limited to major medical centers, valid blood-based biomarkers of Alzheimer disease that are reasonably specific make large-scale epidemiological studies that investigate dementia etiologies in rural or urban and diverse communities feasible,” he added.
Whereas p-tau181 appears to be specific for plaque and tangle disease, NfL is a nonspecific marker of neurodegeneration.
“Each has a role that could be valuable, depending on the circumstance,” said Dr. Knopman. “Plasma NfL has already proved itself useful in frontotemporal degeneration and chronic traumatic encephalopathy, for example.”
He noted that future studies should examine how closely p-tau181 and NfL align with more granular and direct measures of Alzheimer’s disease–related brain pathologies.
“There has got to be some loss of fidelity in detecting abnormality in going from brain tissue to blood, which might siphon off some time-related and severity-related information,” said Dr. Knopman.
“The exact role that plasma p-tau and NfL will play remains to be seen, because the diagnostic information that these biomarkers provide is contingent on the existence of interventions that require specific or nonspecific information about progressive neurodegeneration due to Alzheimer disease,” he added.
The study was funded by grants from the Spanish Instituto de Salud Carlos III, the Brightfocus Foundation, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. Dr. Schöll reported serving on a scientific advisory board for Servier on matters unrelated to this study. Dr. Moscoso and Dr. Knopman have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Type of Alzheimer’s disease with intact memory offers new research paths
They also show some differences in neuropathology to typical patients with Alzheimer’s disease, raising hopes of discovering novel mechanisms that might protect against memory loss in typical forms of the disease.
“We are discovering that Alzheimer’s disease has more than one form. While the typical patient with Alzheimer’s disease will have impaired memory, patients with primary progressive aphasia linked to Alzheimer’s disease are quite different. They have problems with language – they know what they want to say but can’t find the words – but their memory is intact,” said lead author Marsel Mesulam, MD.
“We have found that these patients still show the same levels of neurofibrillary tangles which destroy neurons in the memory part of the brain as typical patients with Alzheimer’s disease, but in patients with primary progressive aphasia Alzheimer’s the nondominant side of this part of the brain showed less atrophy,” added Dr. Mesulam, who is director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University, Chicago. “It appears that these patients are more resilient to the effects of the neurofibrillary tangles.”
The researchers also found that two biomarkers that are established risk factors in typical Alzheimer’s disease do not appear to be risk factors for the primary progressive aphasia (PPA) form of the condition.
“These observations suggest that there are mechanisms that may protect the brain from Alzheimer’s-type damage. Studying these patients with this primary progressive aphasia form of Alzheimer’s disease may give us clues as to where to look for these mechanisms that may lead to new treatments for the memory loss associated with typical Alzheimer’s disease,” Dr. Mesulam commented.
The study was published online in the Jan. 13 issue of Neurology.
PPA is diagnosed when language impairment emerges on a background of preserved memory and behavior, with about 40% of cases representing atypical manifestations of Alzheimer’s disease, the researchers explained.
“While we knew that the memories of people with primary progressive aphasia were not affected at first, we did not know if they maintained their memory functioning over years,” Dr. Mesulam noted.
The current study aimed to investigate whether the memory preservation in PPA linked to Alzheimer’s disease is a consistent core feature or a transient finding confined to initial presentation, and to explore the underlying pathology of the condition.
The researchers searched their database to identify patients with PPA with autopsy or biomarker evidence of Alzheimer’s disease, who also had at least two consecutive visits during which language and memory assessment had been obtained with the same tests. The study included 17 patients with the PPA-type Alzheimer’s disease who compared with 14 patients who had typical Alzheimer’s disease with memory loss.
The authors pointed out that characterization of memory in patients with PPA is challenging because most tests use word lists, and thus patients may fail the test because of their language impairments. To address this issue, they included patients with PPA who had undergone memory tests involving recalling pictures of common objects.
Patients with typical Alzheimer’s disease underwent similar tests but used a list of common words.
A second round of tests was conducted in the primary progressive aphasia group an average of 2.4 years later and in the typical Alzheimer’s disease group an average of 1.7 years later.
Brain scans were also available for the patients with PPA, as well as postmortem evaluations for eight of the PPA cases and all the typical Alzheimer’s disease cases.
Results showed that patients with PPA had no decline in their memory skills when they took the tests a second time. At that point, they had been showing symptoms of the disorder for an average of 6 years. In contrast, their language skills declined significantly during the same period. For typical patients with Alzheimer’s disease, verbal memory and language skills declined with equal severity during the study.
Postmortem results showed that the two groups had comparable degrees of Alzheimer’s disease pathology in the medial temporal lobe – the main area of the brain affected in dementia.
However, MRI scans showed that patients with PPA had an asymmetrical atrophy of the dominant (left) hemisphere with sparing of the right sided medial temporal lobe, indicating a lack of neurodegeneration in the nondominant hemisphere, despite the presence of Alzheimer’s disease pathology.
It was also found that the patients with PPA had significantly lower prevalence of two factors strongly linked to Alzheimer’s disease – TDP-43 pathology and APOE ε4 positivity – than the typical patients with Alzheimer’s disease.
The authors concluded that “primary progressive aphasia Alzheimer’s syndrome offers unique opportunities for exploring the biological foundations of these phenomena that interactively modulate the impact of Alzheimer’s disease neuropathology on cognitive function.”
‘Preservation of cognition is the holy grail’
In an accompanying editorial, Seyed Ahmad Sajjadi, MD, University of California, Irvine; Sharon Ash, PhD, University of Pennsylvania, Philadelphia; and Stefano Cappa, MD, University School for Advanced Studies, Pavia, Italy, said these findings have important implications, “as ultimately, preservation of cognition is the holy grail of research in this area.”
They pointed out that the current observations imply “an uncoupling of neurodegeneration and pathology” in patients with PPA-type Alzheimer’s disease, adding that “it seems reasonable to conclude that neurodegeneration, and not mere presence of pathology, is what correlates with clinical presentation in these patients.”
The editorialists noted that the study has some limitations: the sample size is relatively small, not all patients with PPA-type Alzheimer’s disease underwent autopsy, MRI was only available for the aphasia group, and the two groups had different memory tests for comparison of their recognition memory.
But they concluded that this study “provides important insights about the potential reasons for differential vulnerability of the neural substrate of memory in those with different clinical presentations of Alzheimer’s disease pathology.”
The study was supported by the National Institute on Deafness and Communication Disorders, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Davee Foundation, and the Jeanine Jones Fund.
A version of this article first appeared on Medscape.com.
They also show some differences in neuropathology to typical patients with Alzheimer’s disease, raising hopes of discovering novel mechanisms that might protect against memory loss in typical forms of the disease.
“We are discovering that Alzheimer’s disease has more than one form. While the typical patient with Alzheimer’s disease will have impaired memory, patients with primary progressive aphasia linked to Alzheimer’s disease are quite different. They have problems with language – they know what they want to say but can’t find the words – but their memory is intact,” said lead author Marsel Mesulam, MD.
“We have found that these patients still show the same levels of neurofibrillary tangles which destroy neurons in the memory part of the brain as typical patients with Alzheimer’s disease, but in patients with primary progressive aphasia Alzheimer’s the nondominant side of this part of the brain showed less atrophy,” added Dr. Mesulam, who is director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University, Chicago. “It appears that these patients are more resilient to the effects of the neurofibrillary tangles.”
The researchers also found that two biomarkers that are established risk factors in typical Alzheimer’s disease do not appear to be risk factors for the primary progressive aphasia (PPA) form of the condition.
“These observations suggest that there are mechanisms that may protect the brain from Alzheimer’s-type damage. Studying these patients with this primary progressive aphasia form of Alzheimer’s disease may give us clues as to where to look for these mechanisms that may lead to new treatments for the memory loss associated with typical Alzheimer’s disease,” Dr. Mesulam commented.
The study was published online in the Jan. 13 issue of Neurology.
PPA is diagnosed when language impairment emerges on a background of preserved memory and behavior, with about 40% of cases representing atypical manifestations of Alzheimer’s disease, the researchers explained.
“While we knew that the memories of people with primary progressive aphasia were not affected at first, we did not know if they maintained their memory functioning over years,” Dr. Mesulam noted.
The current study aimed to investigate whether the memory preservation in PPA linked to Alzheimer’s disease is a consistent core feature or a transient finding confined to initial presentation, and to explore the underlying pathology of the condition.
The researchers searched their database to identify patients with PPA with autopsy or biomarker evidence of Alzheimer’s disease, who also had at least two consecutive visits during which language and memory assessment had been obtained with the same tests. The study included 17 patients with the PPA-type Alzheimer’s disease who compared with 14 patients who had typical Alzheimer’s disease with memory loss.
The authors pointed out that characterization of memory in patients with PPA is challenging because most tests use word lists, and thus patients may fail the test because of their language impairments. To address this issue, they included patients with PPA who had undergone memory tests involving recalling pictures of common objects.
Patients with typical Alzheimer’s disease underwent similar tests but used a list of common words.
A second round of tests was conducted in the primary progressive aphasia group an average of 2.4 years later and in the typical Alzheimer’s disease group an average of 1.7 years later.
Brain scans were also available for the patients with PPA, as well as postmortem evaluations for eight of the PPA cases and all the typical Alzheimer’s disease cases.
Results showed that patients with PPA had no decline in their memory skills when they took the tests a second time. At that point, they had been showing symptoms of the disorder for an average of 6 years. In contrast, their language skills declined significantly during the same period. For typical patients with Alzheimer’s disease, verbal memory and language skills declined with equal severity during the study.
Postmortem results showed that the two groups had comparable degrees of Alzheimer’s disease pathology in the medial temporal lobe – the main area of the brain affected in dementia.
However, MRI scans showed that patients with PPA had an asymmetrical atrophy of the dominant (left) hemisphere with sparing of the right sided medial temporal lobe, indicating a lack of neurodegeneration in the nondominant hemisphere, despite the presence of Alzheimer’s disease pathology.
It was also found that the patients with PPA had significantly lower prevalence of two factors strongly linked to Alzheimer’s disease – TDP-43 pathology and APOE ε4 positivity – than the typical patients with Alzheimer’s disease.
The authors concluded that “primary progressive aphasia Alzheimer’s syndrome offers unique opportunities for exploring the biological foundations of these phenomena that interactively modulate the impact of Alzheimer’s disease neuropathology on cognitive function.”
‘Preservation of cognition is the holy grail’
In an accompanying editorial, Seyed Ahmad Sajjadi, MD, University of California, Irvine; Sharon Ash, PhD, University of Pennsylvania, Philadelphia; and Stefano Cappa, MD, University School for Advanced Studies, Pavia, Italy, said these findings have important implications, “as ultimately, preservation of cognition is the holy grail of research in this area.”
They pointed out that the current observations imply “an uncoupling of neurodegeneration and pathology” in patients with PPA-type Alzheimer’s disease, adding that “it seems reasonable to conclude that neurodegeneration, and not mere presence of pathology, is what correlates with clinical presentation in these patients.”
The editorialists noted that the study has some limitations: the sample size is relatively small, not all patients with PPA-type Alzheimer’s disease underwent autopsy, MRI was only available for the aphasia group, and the two groups had different memory tests for comparison of their recognition memory.
But they concluded that this study “provides important insights about the potential reasons for differential vulnerability of the neural substrate of memory in those with different clinical presentations of Alzheimer’s disease pathology.”
The study was supported by the National Institute on Deafness and Communication Disorders, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Davee Foundation, and the Jeanine Jones Fund.
A version of this article first appeared on Medscape.com.
They also show some differences in neuropathology to typical patients with Alzheimer’s disease, raising hopes of discovering novel mechanisms that might protect against memory loss in typical forms of the disease.
“We are discovering that Alzheimer’s disease has more than one form. While the typical patient with Alzheimer’s disease will have impaired memory, patients with primary progressive aphasia linked to Alzheimer’s disease are quite different. They have problems with language – they know what they want to say but can’t find the words – but their memory is intact,” said lead author Marsel Mesulam, MD.
“We have found that these patients still show the same levels of neurofibrillary tangles which destroy neurons in the memory part of the brain as typical patients with Alzheimer’s disease, but in patients with primary progressive aphasia Alzheimer’s the nondominant side of this part of the brain showed less atrophy,” added Dr. Mesulam, who is director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University, Chicago. “It appears that these patients are more resilient to the effects of the neurofibrillary tangles.”
The researchers also found that two biomarkers that are established risk factors in typical Alzheimer’s disease do not appear to be risk factors for the primary progressive aphasia (PPA) form of the condition.
“These observations suggest that there are mechanisms that may protect the brain from Alzheimer’s-type damage. Studying these patients with this primary progressive aphasia form of Alzheimer’s disease may give us clues as to where to look for these mechanisms that may lead to new treatments for the memory loss associated with typical Alzheimer’s disease,” Dr. Mesulam commented.
The study was published online in the Jan. 13 issue of Neurology.
PPA is diagnosed when language impairment emerges on a background of preserved memory and behavior, with about 40% of cases representing atypical manifestations of Alzheimer’s disease, the researchers explained.
“While we knew that the memories of people with primary progressive aphasia were not affected at first, we did not know if they maintained their memory functioning over years,” Dr. Mesulam noted.
The current study aimed to investigate whether the memory preservation in PPA linked to Alzheimer’s disease is a consistent core feature or a transient finding confined to initial presentation, and to explore the underlying pathology of the condition.
The researchers searched their database to identify patients with PPA with autopsy or biomarker evidence of Alzheimer’s disease, who also had at least two consecutive visits during which language and memory assessment had been obtained with the same tests. The study included 17 patients with the PPA-type Alzheimer’s disease who compared with 14 patients who had typical Alzheimer’s disease with memory loss.
The authors pointed out that characterization of memory in patients with PPA is challenging because most tests use word lists, and thus patients may fail the test because of their language impairments. To address this issue, they included patients with PPA who had undergone memory tests involving recalling pictures of common objects.
Patients with typical Alzheimer’s disease underwent similar tests but used a list of common words.
A second round of tests was conducted in the primary progressive aphasia group an average of 2.4 years later and in the typical Alzheimer’s disease group an average of 1.7 years later.
Brain scans were also available for the patients with PPA, as well as postmortem evaluations for eight of the PPA cases and all the typical Alzheimer’s disease cases.
Results showed that patients with PPA had no decline in their memory skills when they took the tests a second time. At that point, they had been showing symptoms of the disorder for an average of 6 years. In contrast, their language skills declined significantly during the same period. For typical patients with Alzheimer’s disease, verbal memory and language skills declined with equal severity during the study.
Postmortem results showed that the two groups had comparable degrees of Alzheimer’s disease pathology in the medial temporal lobe – the main area of the brain affected in dementia.
However, MRI scans showed that patients with PPA had an asymmetrical atrophy of the dominant (left) hemisphere with sparing of the right sided medial temporal lobe, indicating a lack of neurodegeneration in the nondominant hemisphere, despite the presence of Alzheimer’s disease pathology.
It was also found that the patients with PPA had significantly lower prevalence of two factors strongly linked to Alzheimer’s disease – TDP-43 pathology and APOE ε4 positivity – than the typical patients with Alzheimer’s disease.
The authors concluded that “primary progressive aphasia Alzheimer’s syndrome offers unique opportunities for exploring the biological foundations of these phenomena that interactively modulate the impact of Alzheimer’s disease neuropathology on cognitive function.”
‘Preservation of cognition is the holy grail’
In an accompanying editorial, Seyed Ahmad Sajjadi, MD, University of California, Irvine; Sharon Ash, PhD, University of Pennsylvania, Philadelphia; and Stefano Cappa, MD, University School for Advanced Studies, Pavia, Italy, said these findings have important implications, “as ultimately, preservation of cognition is the holy grail of research in this area.”
They pointed out that the current observations imply “an uncoupling of neurodegeneration and pathology” in patients with PPA-type Alzheimer’s disease, adding that “it seems reasonable to conclude that neurodegeneration, and not mere presence of pathology, is what correlates with clinical presentation in these patients.”
The editorialists noted that the study has some limitations: the sample size is relatively small, not all patients with PPA-type Alzheimer’s disease underwent autopsy, MRI was only available for the aphasia group, and the two groups had different memory tests for comparison of their recognition memory.
But they concluded that this study “provides important insights about the potential reasons for differential vulnerability of the neural substrate of memory in those with different clinical presentations of Alzheimer’s disease pathology.”
The study was supported by the National Institute on Deafness and Communication Disorders, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Davee Foundation, and the Jeanine Jones Fund.
A version of this article first appeared on Medscape.com.