Patients who are on hemodialysis and who have cancer present a “unique challenge,” say clinicians from Dartmouth-Hitchcock in New Hampshire.

Patients with end-stage renal disease (ESRD) are at risk of drug accumulation and toxicity. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are “scant,” the clinicians say. They cite a study that found 72% of dialysis patients receiving anticancer drugs needed dosage adjustments for at least 1 drug. The study researchers also found a significant number of chemotherapy drugs for which there were no available recommendations in dialysis patients.

However, a safe and effective alternative for these patients may exist. The clinicians report on a case—to the best of their knowledge, the first such—of a patient with metastatic melanoma who was successfully treated with pembrolizumab while on hemodialysis.

The patient, who had diabetes and ESRD, also had melanoma in his ear, which metastasized. After discussing his therapeutic options—including the limited data on available immunotherapy drugs—clinicians and the patient agreed to proceed with pembrolizumab, an IgG4-κ human antiprogrammed cell death protein 1 (PD-1) monoclonal antibody. Pembrolizumab has been shown to improve survival rates in patients with melanoma, although it had not been reported in patients with melanoma on dialysis.

The patient received pembrolizumab 2 mg/kg/dose, repeated every 3 weeks. After 1 dose, his abdominal pain and appetite improved. Serum lactate dehydrogenase dropped from 1,182 to 354 units/L. He continued on dialysis 3 times a week with stable serum creatinine levels. After 3 cycles, the computerized tomography scan showed the pulmonary nodules had resolved,  and retroperitoneal lymphadenopathy was significantly reduced. After 10 cycles, he was in complete remission.

Pembrolizumab has distinct benefits for patients like theirs, the clinicians suggest. For one, the molecular weight of the antibody means it is not dialysable, so ultrafiltration (reducing drug exposure) is not the issue it might be. The drug can likely be given without regard to the timing of dialysis. Another benefit for these patients who are usually immunocompromised is that PD-1 antibodies “disrupt” the interactions that create an “immune-suppressive tumor microenvironment” and allow T-cell antitumor activity, the clinicians say.

Their report demonstrates that PD-1 antibodies can be effective in dialysis-dependent ESRD, they say, but add that further research into the induced immune response is warranted. In clinical trials, a small number of patients on pembrolizumab (0.4%) developed immune-mediated nephritis. That might not be as crucial for patients who are already on hemodialysis, the clinicians note, but they caution that the adverse effect (AE) could be a risk for patients with normal renal function or chronic kidney disease. However, their patient experienced no pembrolizumab-related AEs other than mild fatigue.

Source:

Chang R, Shirai K. BMJ Case Rep. 2016; pii: bcr2016216426.

doi: 10.1136/bcr-2016-216426.

Patients who are on hemodialysis and who have cancer present a “unique challenge,” say clinicians from Dartmouth-Hitchcock in New Hampshire.

Patients with end-stage renal disease (ESRD) are at risk of drug accumulation and toxicity. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are “scant,” the clinicians say. They cite a study that found 72% of dialysis patients receiving anticancer drugs needed dosage adjustments for at least 1 drug. The study researchers also found a significant number of chemotherapy drugs for which there were no available recommendations in dialysis patients.

However, a safe and effective alternative for these patients may exist. The clinicians report on a case—to the best of their knowledge, the first such—of a patient with metastatic melanoma who was successfully treated with pembrolizumab while on hemodialysis.

The patient, who had diabetes and ESRD, also had melanoma in his ear, which metastasized. After discussing his therapeutic options—including the limited data on available immunotherapy drugs—clinicians and the patient agreed to proceed with pembrolizumab, an IgG4-κ human antiprogrammed cell death protein 1 (PD-1) monoclonal antibody. Pembrolizumab has been shown to improve survival rates in patients with melanoma, although it had not been reported in patients with melanoma on dialysis.

The patient received pembrolizumab 2 mg/kg/dose, repeated every 3 weeks. After 1 dose, his abdominal pain and appetite improved. Serum lactate dehydrogenase dropped from 1,182 to 354 units/L. He continued on dialysis 3 times a week with stable serum creatinine levels. After 3 cycles, the computerized tomography scan showed the pulmonary nodules had resolved,  and retroperitoneal lymphadenopathy was significantly reduced. After 10 cycles, he was in complete remission.

Pembrolizumab has distinct benefits for patients like theirs, the clinicians suggest. For one, the molecular weight of the antibody means it is not dialysable, so ultrafiltration (reducing drug exposure) is not the issue it might be. The drug can likely be given without regard to the timing of dialysis. Another benefit for these patients who are usually immunocompromised is that PD-1 antibodies “disrupt” the interactions that create an “immune-suppressive tumor microenvironment” and allow T-cell antitumor activity, the clinicians say.

Their report demonstrates that PD-1 antibodies can be effective in dialysis-dependent ESRD, they say, but add that further research into the induced immune response is warranted. In clinical trials, a small number of patients on pembrolizumab (0.4%) developed immune-mediated nephritis. That might not be as crucial for patients who are already on hemodialysis, the clinicians note, but they caution that the adverse effect (AE) could be a risk for patients with normal renal function or chronic kidney disease. However, their patient experienced no pembrolizumab-related AEs other than mild fatigue.

Source:

Chang R, Shirai K. BMJ Case Rep. 2016; pii: bcr2016216426.

doi: 10.1136/bcr-2016-216426.

Patients who are on hemodialysis and who have cancer present a “unique challenge,” say clinicians from Dartmouth-Hitchcock in New Hampshire.

Patients with end-stage renal disease (ESRD) are at risk of drug accumulation and toxicity. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are “scant,” the clinicians say. They cite a study that found 72% of dialysis patients receiving anticancer drugs needed dosage adjustments for at least 1 drug. The study researchers also found a significant number of chemotherapy drugs for which there were no available recommendations in dialysis patients.

However, a safe and effective alternative for these patients may exist. The clinicians report on a case—to the best of their knowledge, the first such—of a patient with metastatic melanoma who was successfully treated with pembrolizumab while on hemodialysis.

The patient, who had diabetes and ESRD, also had melanoma in his ear, which metastasized. After discussing his therapeutic options—including the limited data on available immunotherapy drugs—clinicians and the patient agreed to proceed with pembrolizumab, an IgG4-κ human antiprogrammed cell death protein 1 (PD-1) monoclonal antibody. Pembrolizumab has been shown to improve survival rates in patients with melanoma, although it had not been reported in patients with melanoma on dialysis.

The patient received pembrolizumab 2 mg/kg/dose, repeated every 3 weeks. After 1 dose, his abdominal pain and appetite improved. Serum lactate dehydrogenase dropped from 1,182 to 354 units/L. He continued on dialysis 3 times a week with stable serum creatinine levels. After 3 cycles, the computerized tomography scan showed the pulmonary nodules had resolved,  and retroperitoneal lymphadenopathy was significantly reduced. After 10 cycles, he was in complete remission.

Pembrolizumab has distinct benefits for patients like theirs, the clinicians suggest. For one, the molecular weight of the antibody means it is not dialysable, so ultrafiltration (reducing drug exposure) is not the issue it might be. The drug can likely be given without regard to the timing of dialysis. Another benefit for these patients who are usually immunocompromised is that PD-1 antibodies “disrupt” the interactions that create an “immune-suppressive tumor microenvironment” and allow T-cell antitumor activity, the clinicians say.

Their report demonstrates that PD-1 antibodies can be effective in dialysis-dependent ESRD, they say, but add that further research into the induced immune response is warranted. In clinical trials, a small number of patients on pembrolizumab (0.4%) developed immune-mediated nephritis. That might not be as crucial for patients who are already on hemodialysis, the clinicians note, but they caution that the adverse effect (AE) could be a risk for patients with normal renal function or chronic kidney disease. However, their patient experienced no pembrolizumab-related AEs other than mild fatigue.

Source:

Chang R, Shirai K. BMJ Case Rep. 2016; pii: bcr2016216426.

doi: 10.1136/bcr-2016-216426.

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Photo by Bill Branson

New research suggests survivors of childhood cancer can incur high out-of-pocket medical costs into adulthood and may forgo healthcare to lessen this financial burden.

The study showed that childhood cancer survivors (CCSs) were more likely than non-CCSs to have out-of-pocket medical costs that were at least 10% of their annual income.

And these high costs were associated with delaying care or skipping it altogether.

These findings were published in the Journal of Clinical Oncology.

“Survivors who reported spending a higher percentage of their income on out-of-pocket medical costs were not only more likely to report financial burden, they also were at risk for undertaking behaviors potentially detrimental to their health in order to save money,” said study author Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston.

“While studies have identified associations between financial burden and patients’ treatment outcomes, quality of life, and even survival among adults with cancer, as far as we know, this is the first to report these associations in survivors of childhood cancer.”

For this research, Dr Nipp and his colleagues surveyed participants in the Childhood Cancer Survivor Study. This included adults who had been treated for childhood cancers between 1970 and 1986 along with a control group of siblings not affected by cancer.

In 2011 and 2012, participants were asked to provide information about their health insurance, the out-of-pocket healthcare costs they paid during the previous year, and sociodemographic information such as annual income and employment status.

The researchers also asked participants whether medical costs posed a financial burden and, if so, what measures they had taken to deal with that burden.

Study population

The researchers received complete responses from 580 CCSs and 173 of their siblings without a history of cancer. The most common cancer diagnosis was leukemia (33%), followed by Hodgkin lymphoma (14%), while non-Hodgkin lymphoma was less common (7%).

CCSs were a mean of 30.2 years from diagnosis. Use of chemotherapy (77%), radiation (66%), and surgery (81%) were common. Few patients had cancer recurrence (13%) or second cancers (5%).

There was no significant difference between CCSs and their siblings with regard to age at the time of the survey (P=0.071), household income (P=0.053), education (P=0.345), health insurance status (P=0.317), or having at least 1 hospitalization in the past year (P=0.270).

However, CCSs were significantly more likely than siblings to have chronic health conditions (P<0.001). Forty percent of CCSs had severe or life-threatening chronic conditions, compared to 17% of siblings.

Seventy-six percent of CCSs and 80% of siblings were employed. Twenty-nine percent of CCSs and 39% of siblings had household incomes exceeding $100,000. Twelve percent of CCSs and 5% of siblings had household incomes below $20,000.

Ninety-one percent of CCSs and 93% of siblings were insured. Most subjects in both groups (81% and 87%, respectively) had employer-sponsored insurance.

Results

CCSs were significantly more likely than their siblings to have out-of-pocket medical costs that were at least 10% of their annual income—10% and 3%, respectively (P<0.001).

Among CCSs, those with higher out-of-pocket costs (≥10% vs <10% of income) were more likely to have household incomes below $50,000 (odds ratio [OR]=5.5) and to report being hospitalized in the past year (OR=2.3).

CCSs with a higher percentage of their income spent on out-of-pocket costs were also more likely to:

• Have problems paying their medical bills (OR=8.8)
• Report inability to pay for basic costs of living such as food, heat, or rent (OR=6.1)
• Defer healthcare for a medical problem (OR=3.1)
• Skip a test, treatment, or follow-up (OR=2.1)
• Consider filing for bankruptcy (OR=6.4).

“A more comprehensive understanding of the relationship between high out-of-pocket medical costs and the adverse effects of increased financial burden on cancer survivors could be instrumental in helping us identify those at risk for higher costs to help us address their financial challenges and improve health outcomes,” Dr Nipp said.

“It could also help inform policy changes to help meet the unique needs of cancer survivors and improve our understanding of how both higher costs and resulting financial burden influence patients’ approach to their medical care and decision-making.”

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Image by Lance Liotta

Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).

The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.

This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.

Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.

“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”

Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.

The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.

To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.

So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.

The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.

This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.

In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.

“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.

“So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”

The researchers said further studies are needed to better understand the potential clinical implications of these findings.

However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of this study might offer an explanation.

“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of TET2,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. Because these patients only have one good copy of TET2 left, they need to maximize the residual TET2 tumor-suppressor activity to protect themselves from cancer.” 

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved new product strengths for the factor VIII therapy simoctocog alfa (NUWIQ®).

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is FDA-approved to treat adults and children with hemophilia A. This includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Now, the FDA has approved single-dose simoctocog alfa vial strengths of 2500, 3000, and 4000 International Units (IU), which will be available for order in the US starting September 2017.

These new vial strengths will be provided in addition to the already available strengths of 250, 500, 1000, and 2000 IU.

“The new vial options will benefit patients, physicians, and healthcare professionals by providing greater treatment flexibility and convenience,” said Flemming Nielsen, president of Octapharma USA, makers of simoctocog alfa.

According to Octapharma, the additional vial strengths offer benefits beyond potentially reducing the number of vials used per patient. The new vial sizes may benefit heavier patients who could use fewer product vials and, in some cases, just one vial.

More vial options will increase dosing flexibility by allowing physicians to select various vial combinations to align closer to the prescribed dose. The new vial sizes could be particularly beneficial to patients using a pharmacokinetic (PK)-guided, personalized prophylaxis approach.

Results of Octapharma’s clinical trial on the PK-guided dosing with simoctocog alfa were published in Haemophilia in April.

This study, known as GENA-21 or NuPreviq, enrolled 66 previously treated adults with severe hemophilia A. Patients were originally started on infusions 3 times a week or every other day. Subsequent dosing intervals were then determined based on individual PK data.

The median dosing interval with PK-guided prophylaxis was 3.5 days, and 57% of patients were able to decrease infusions to twice-weekly or less.

The median weekly prophylaxis dose was reduced by 7.2%, from 100.0 IU kg⁻¹ with standard prophylaxis to 92.8 IU kg⁻¹ during the last 2 months of personalized prophylaxis.

For all bleeds, the mean annualized bleeding rate (ABR) during personalized prophylaxis was 1.45, and the median was 0 (interquartile range, [IQR]: 0, 1.9).

For spontaneous bleeds, the mean ABR was 0.79, and the median was 0 (IQR: 0, 0). For joint bleeds, the mean ABR was 0.91, and the median was 0 (IQR: 0, 0).

None of the patients developed FVIII inhibitors. There were no treatment-related serious or severe adverse events, clinically significant abnormalities in laboratory parameters, or cases of thromboembolism.

The ongoing trial GENA-21b is designed to confirm the results of GENA-21.

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved new product strengths for the factor VIII therapy simoctocog alfa (NUWIQ®).

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is FDA-approved to treat adults and children with hemophilia A. This includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Now, the FDA has approved single-dose simoctocog alfa vial strengths of 2500, 3000, and 4000 International Units (IU), which will be available for order in the US starting September 2017.

These new vial strengths will be provided in addition to the already available strengths of 250, 500, 1000, and 2000 IU.

“The new vial options will benefit patients, physicians, and healthcare professionals by providing greater treatment flexibility and convenience,” said Flemming Nielsen, president of Octapharma USA, makers of simoctocog alfa.

According to Octapharma, the additional vial strengths offer benefits beyond potentially reducing the number of vials used per patient. The new vial sizes may benefit heavier patients who could use fewer product vials and, in some cases, just one vial.

More vial options will increase dosing flexibility by allowing physicians to select various vial combinations to align closer to the prescribed dose. The new vial sizes could be particularly beneficial to patients using a pharmacokinetic (PK)-guided, personalized prophylaxis approach.

Results of Octapharma’s clinical trial on the PK-guided dosing with simoctocog alfa were published in Haemophilia in April.

This study, known as GENA-21 or NuPreviq, enrolled 66 previously treated adults with severe hemophilia A. Patients were originally started on infusions 3 times a week or every other day. Subsequent dosing intervals were then determined based on individual PK data.

The median dosing interval with PK-guided prophylaxis was 3.5 days, and 57% of patients were able to decrease infusions to twice-weekly or less.

The median weekly prophylaxis dose was reduced by 7.2%, from 100.0 IU kg⁻¹ with standard prophylaxis to 92.8 IU kg⁻¹ during the last 2 months of personalized prophylaxis.

For all bleeds, the mean annualized bleeding rate (ABR) during personalized prophylaxis was 1.45, and the median was 0 (interquartile range, [IQR]: 0, 1.9).

For spontaneous bleeds, the mean ABR was 0.79, and the median was 0 (IQR: 0, 0). For joint bleeds, the mean ABR was 0.91, and the median was 0 (IQR: 0, 0).

None of the patients developed FVIII inhibitors. There were no treatment-related serious or severe adverse events, clinically significant abnormalities in laboratory parameters, or cases of thromboembolism.

The ongoing trial GENA-21b is designed to confirm the results of GENA-21.

Photo from Business Wire

The US Food and Drug Administration (FDA) has approved new product strengths for the factor VIII therapy simoctocog alfa (NUWIQ®).

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is FDA-approved to treat adults and children with hemophilia A. This includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Now, the FDA has approved single-dose simoctocog alfa vial strengths of 2500, 3000, and 4000 International Units (IU), which will be available for order in the US starting September 2017.

These new vial strengths will be provided in addition to the already available strengths of 250, 500, 1000, and 2000 IU.

“The new vial options will benefit patients, physicians, and healthcare professionals by providing greater treatment flexibility and convenience,” said Flemming Nielsen, president of Octapharma USA, makers of simoctocog alfa.

According to Octapharma, the additional vial strengths offer benefits beyond potentially reducing the number of vials used per patient. The new vial sizes may benefit heavier patients who could use fewer product vials and, in some cases, just one vial.

More vial options will increase dosing flexibility by allowing physicians to select various vial combinations to align closer to the prescribed dose. The new vial sizes could be particularly beneficial to patients using a pharmacokinetic (PK)-guided, personalized prophylaxis approach.

Results of Octapharma’s clinical trial on the PK-guided dosing with simoctocog alfa were published in Haemophilia in April.

This study, known as GENA-21 or NuPreviq, enrolled 66 previously treated adults with severe hemophilia A. Patients were originally started on infusions 3 times a week or every other day. Subsequent dosing intervals were then determined based on individual PK data.

The median dosing interval with PK-guided prophylaxis was 3.5 days, and 57% of patients were able to decrease infusions to twice-weekly or less.

The median weekly prophylaxis dose was reduced by 7.2%, from 100.0 IU kg⁻¹ with standard prophylaxis to 92.8 IU kg⁻¹ during the last 2 months of personalized prophylaxis.

For all bleeds, the mean annualized bleeding rate (ABR) during personalized prophylaxis was 1.45, and the median was 0 (interquartile range, [IQR]: 0, 1.9).

For spontaneous bleeds, the mean ABR was 0.79, and the median was 0 (IQR: 0, 0). For joint bleeds, the mean ABR was 0.91, and the median was 0 (IQR: 0, 0).

None of the patients developed FVIII inhibitors. There were no treatment-related serious or severe adverse events, clinically significant abnormalities in laboratory parameters, or cases of thromboembolism.

The ongoing trial GENA-21b is designed to confirm the results of GENA-21.

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP suspected pustular psoriasis, which was confirmed by a dermatologist the patient saw the following day. The dermatologist confirmed this diagnosis by performing a 4-mm punch biopsy, which included an area of new pustules on the patient’s arm. When a rash is extensive, it’s best to biopsy new lesions from the upper body, rather than old lesions below the waist.

Pustular psoriasis can lead to confluent pustules, a condition in which the skin peels off in sheets, resulting in dehydration and a risk of sepsis. This is why you shouldn’t prescribe oral prednisone for any rash before you know that it’s not psoriasis. While oral prednisone may be an effective treatment for many types of dermatitis, it can exacerbate psoriasis (as it did with this patient), and is therefore not an effective or safe treatment for it.

Knowing that pustular psoriasis can become a dermatologic emergency, the FP prescribed oral cyclosporine for the most rapid result. The patient’s blood pressure and kidney function were normal, so it was only necessary for the FP to order baseline laboratory tests. At the follow-up appointment 2 days later, the patient’s condition was already improving and there were no new pustules. Her vital signs remained stable and the pathology report confirmed pustular psoriasis.

The dermatologist planned to transition the patient from cyclosporine to acitretin, determining it was safe to prescribe an oral retinoid. The patient’s hysterectomy 2 years earlier also eliminated concerns about acitretin’s teratogenic potency. The dermatologist prescribed acitretin with directions for the patient to begin taking it in one week, tapering off the cyclosporine once the pustular psoriasis was significantly better.

After a month, the patient was off of cyclosporine completely. Her skin was clear while using daily acitretin. Monitoring of lab tests did not show any adverse effects of the patient using these 2 potentially toxic medications.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Psoriasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 878-895.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Clinical Question: What is the epidemiology of meningitis and encephalitis in adults in the United States?

Background: Previous epidemiologic studies have been smaller with less clinical information available and without steroid usage rates.

Study Design: A retrospective database review.

Setting: The Premier HealthCare Database, including hospitals of all types and sizes.

Dr. Hall is an assistant professor in the University of Kentucky division of hospital medicine and pediatrics.

Clinical Question: What is the epidemiology of meningitis and encephalitis in adults in the United States?

Background: Previous epidemiologic studies have been smaller with less clinical information available and without steroid usage rates.

Study Design: A retrospective database review.

Setting: The Premier HealthCare Database, including hospitals of all types and sizes.

Dr. Hall is an assistant professor in the University of Kentucky division of hospital medicine and pediatrics.

Clinical Question: What is the epidemiology of meningitis and encephalitis in adults in the United States?

Background: Previous epidemiologic studies have been smaller with less clinical information available and without steroid usage rates.

Study Design: A retrospective database review.

Setting: The Premier HealthCare Database, including hospitals of all types and sizes.

Dr. Hall is an assistant professor in the University of Kentucky division of hospital medicine and pediatrics.

Remediation programs and program director attitudes can make the difference in attrition rates among general surgery residents, according to a survey-based study.

A study by the Association of American Medical Colleges, projects a shortage of 29,000 general surgeons by 2030. Some residency programs are taking steps lower program dropout rates, which has been reported as high as 26% in some programs, according to Alexander Schwed, MD, general surgeon at Harbor–University of California, Los Angeles Medical Center.

*Correction, 10/26/17: An earlier version of this article misstated the number of incoming residents in the program.

[email protected]

On Twitter @eaztweets

Remediation programs and program director attitudes can make the difference in attrition rates among general surgery residents, according to a survey-based study.

A study by the Association of American Medical Colleges, projects a shortage of 29,000 general surgeons by 2030. Some residency programs are taking steps lower program dropout rates, which has been reported as high as 26% in some programs, according to Alexander Schwed, MD, general surgeon at Harbor–University of California, Los Angeles Medical Center.

*Correction, 10/26/17: An earlier version of this article misstated the number of incoming residents in the program.

[email protected]

On Twitter @eaztweets

Remediation programs and program director attitudes can make the difference in attrition rates among general surgery residents, according to a survey-based study.

A study by the Association of American Medical Colleges, projects a shortage of 29,000 general surgeons by 2030. Some residency programs are taking steps lower program dropout rates, which has been reported as high as 26% in some programs, according to Alexander Schwed, MD, general surgeon at Harbor–University of California, Los Angeles Medical Center.

*Correction, 10/26/17: An earlier version of this article misstated the number of incoming residents in the program.

[email protected]

On Twitter @eaztweets

I’m a doctor, specifically a neurologist.

I’m also a father with three kids.

I’m also a small business owner and part of the American economy. My practice is small, but provides jobs to two awesome women and in doing so allows them to have insurance, raise their families with job security, own homes, and contribute to the economy. I’m not required to by law, but I provide both with insurance coverage and a retirement plan. I pay my taxes on time and to the penny.

I’m a third-generation American, and a first-generation native Arizonan.

I’m a Phoenix Suns, ASU Sun Devils, and Creighton Bluejays basketball fan.

And, somewhere in all of the above, I’m Jewish.

Didier Kobi/Thinkstock

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m a doctor, specifically a neurologist.

I’m also a father with three kids.

I’m also a small business owner and part of the American economy. My practice is small, but provides jobs to two awesome women and in doing so allows them to have insurance, raise their families with job security, own homes, and contribute to the economy. I’m not required to by law, but I provide both with insurance coverage and a retirement plan. I pay my taxes on time and to the penny.

I’m a third-generation American, and a first-generation native Arizonan.

I’m a Phoenix Suns, ASU Sun Devils, and Creighton Bluejays basketball fan.

And, somewhere in all of the above, I’m Jewish.

Didier Kobi/Thinkstock

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m a doctor, specifically a neurologist.

I’m also a father with three kids.

I’m also a small business owner and part of the American economy. My practice is small, but provides jobs to two awesome women and in doing so allows them to have insurance, raise their families with job security, own homes, and contribute to the economy. I’m not required to by law, but I provide both with insurance coverage and a retirement plan. I pay my taxes on time and to the penny.

I’m a third-generation American, and a first-generation native Arizonan.

I’m a Phoenix Suns, ASU Sun Devils, and Creighton Bluejays basketball fan.

And, somewhere in all of the above, I’m Jewish.

Didier Kobi/Thinkstock

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

LONDON – A 3-month diet comprised of 70% fat improved cognition in Alzheimer’s disease patients better than any anti-amyloid drug that has ever been tested.

In a small pilot study, Alzheimer’s patients who followed the University of Kansas’s ketogenic diet program improved an average of 4 points on one of the most important cognitive assessments in dementia care, the Alzheimer’s Disease Assessment Scale–cognitive domain (ADAS-cog). Not only was this gain statistically significant, but it reached a level that clinical trialists believe to be clinically meaningful, and it was similar to the gains that won Food and Drug Administration approval for donepezil in 1996, according to Russell Swerdlow, MD, director of the University of Kansas Alzheimer’s Disease Center in Fairway.

Diet and dementia

Emerging evidence suggests that modifying diet can help prevent Alzheimer’s and may even help AD patients think and function better. But this research has largely focused on the heart-healthy diets already proven successful in preventing and treating hypertension, diabetes, and cardiovascular disease. Most notably, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet cut the risk of AD by up to 53% (Alzheimers Dement. 2015 Sep;11[9]:1007-14) and also slowed aging-related cognitive decline (Alzheimers Dement. 2015 Sep; 11[9]:1015-22).

MIND is a combination of the low-salt, plant-focused DASH diet, and the heart-healthy Mediterranean diet. It is a moderate-fat plan, with a ratio of 33% fat, 38% carbohydrates, and 26% protein. Ideally, only 3% of the fat should be saturated, so MIND draws on olive oil, nuts, and other foods with monounsaturated fats, largely eschewing animal fats. It’s generally considered fairly easy to follow, since it allows a wide variety of whole grains, beans, nuts, fruits, vegetables, salads, fish, and poultry. Butter, red meat, fried foods, full-fat dairy, and fast foods are strict no-nos.

A ketogenic diet, however, turns MIND on its head. With a 70% fat, 20% protein, 10% carbohydrate ratio, a typical ketogenic diet nearly eliminates most fruits, and virtually all starchy vegetables, beans, and grains. It does, however, incorporate a large amount of fat from many sources, including olive oil, butter, cream, eggs, nuts, all kinds of meat, and fish. For a ketogenic diet, Dr. Swerdlow said, the ratio of fat to protein and carbs is more critical than the source of the fat.

MIND was designed to prevent the cardiovascular and endocrine disorders than predispose to dementia over the long term. But a ketogenic diet for patients with Alzheimer’s acutely manipulates the brain’s energy metabolism system, forcing it to use ketone bodies instead of glucose for fuel.

In normal energy metabolism, carbohydrates provide a ready supply of glucose, the brain’s primary fuel. When carbs are limited or absent, serum insulin decreases and glucagon increases. This promotes lipolysis. Ketones (primarily beta-hydroxybutyrate and acetoacetate) are formed in the liver from the newly released fatty acids, and released into the circulation, including into the brain during times of decreased glucose availability – a state characteristic of Alzheimer’s disease.

Induced ketogenesis trial

Inducing ketosis through diet seems to help correct the normal, age-related decline in the brain’s ability to use glucose, said Stephen Cunnane, PhD, who also presented ketogenic intervention results at AAIC. “Cognitively normal, healthy older adults experience a 10% reduction in the brain’s ability to metabolize glucose compared to healthy young people,” he said in an interview. But this decline accelerates as Alzheimer’s hits. Those with early AD have a 20% decrement in glucose utilization, compared with healthy elders.

Details of the KDRAFT study

The BENEFIC study looked only at the effects of an MCT supplement, which may not deliver all the metabolic benefits of a ketogenic diet. KDRAFT, however, employed both, and assessed not only cognitive outcomes and adverse effects, but the practical matter of whether AD patients and their caregivers could implement the diet and stick to it.

Couples recruited into the trial met with a dietitian who explained the importance of sticking with the strict fat:carb:protein ratio. It’s not easy to stay in that zone, Dr. Swerdlow said, and the MCT supplement really helps there.

“Adding the MCT, which is typically done for the ketogenic diet in epilepsy, increases the fat intake so you can tolerate a bit more carbohydrate and still remain in ketosis. MCT therefore makes it easier to successfully do the diet, if we define success by time in ketosis. Ultimately, it is an iterative diet. You check your urine, and if you are in ketosis, you are doing well. If you are not in ketosis, you have to increase your fat intake, decrease your carb intake, or both.”

The study comprised 15 patients (7 with very mild AD, 4 with mild, and 4 with moderate disease). All patients were instructed to remain on their current medications for Alzheimer’s disease for the duration of the study if they were taking any. All of the patients with moderate AD and one with very mild AD dropped out of the study within the first month, citing caregiver burden. The supplement was in the form of an oil, not an emulsion like the BENEFIC supplement, and it caused diarrhea and nausea in five subjects, although none discontinued because of that.

“We found that a slow titration of the oil could deal with the GI issues. Rather, the primary deal-breaker seemed to be the stress of planning the menus and preparing the meals.”

One patient discontinued his cholinesterase inhibitor during the study, for unknown reasons. His cognitive scores declined, but was still included in the diet-compliant analysis.

The diet didn’t affect weight, blood pressure, insulin sensitivity or resistance, or glucose level, but the intervention was short-lived. Nor were there any significant changes in high-density, low-density, or total cholesterol. Liver enzymes were stable, too.

“The only thing that changed was that they really did increase their fat and decrease their carb intake,” Dr. Swerdlow said. Daily fat jumped from 91 g to 167 g, and carbs dropped from 201 g to 46 g.

Almost everyone who stuck with the diet achieved and maintained ketosis during the study, although with varying degrees of success. “Many only had a trace amount of urinary ketones,” Dr. Swerdlow said. The investigators tracked serum beta hydroxybutyrate levels every month as well, and those measures also confirmed ketosis in the group as a whole, although some patients fluctuated in and out of the state.

The cognitive changes were striking, he said. In the 10-patient analysis, ADAS-cog scores improved by an average of 4.1 points. The results were better when Dr. Swerdlow excluded the patient who stopped his cholinesterase inhibitor medication. In that nine-patient group, the ADAS-cog improved an average of 5.3 points.

While urging caution over the small sample size and lack of a control comparator, Dr. Swerdlow expressed deep satisfaction over the outcomes. A clinician as well as a researcher, he is accustomed to the slow but inexorable decline of AD patients.

“I’m going to try to relate the impression you get in the clinic with these scores,” he said. “Very rarely, but sometimes, with a cholinesterase inhibitor in patients, we’ll see something like a 7-point change. That’s a fantastic response, an improvement you can see across the room. A change of 2 points really doesn’t look that much different, although caregivers will tell you there is a subtle change, maybe a little more focus. The average we got in our 10 subjects was a 4-point improvement. That’s impressive. And a 5-point change is like rolling the clock back by a year.”

The improvements didn’t last, though. A 1-month washout period followed the intervention. By the end, both ADAS-cog and Mini-Mental State Examination scores had returned to their baseline levels. At the end of the study, a few of the patients and their partners expressed their intent to resume the diet, but the investigators do not know whether this indeed happened. Still, the results are encouraging enough that, like Dr. Cunnane, Dr. Swerdlow hopes to conduct a larger, longer study – one that would include a control group.

Future investigations of the ketogenic diet in AD might do well to also include an exercise component, both researchers mentioned. In addition to starvation, ketogenic dieting, and MCT supplementation, exercise is an effective way to induce ketogenesis.

“Exercise produces ketones, but most importantly, it increases the capacity of the brain to use ketones,” Dr. Cunnane said. The connection may help explain some of the cognitive benefits seen in exercise trials in patients with MCI and AD.

“This raises the possibility that if in fact exercise benefits the brain, ketone bodies may mediate some of that effect,” Dr. Swerdlow said. “Could exercise potentiate the ketosis from the diet? That is possible, and maybe using these interventions in conjunction would be synergistic. At this point, we are just happy to show the diet is feasible, if even for a limited period.”

Implementing KDRAFT: Research team dishes the skinny on fats

The KDRAFT study diet is surprisingly flexible despite its strict ratio of fat to protein and carbohydrate, according to the University of Kansas research team that implemented it. It only took a few counseling sessions to get most study participants enthusiastically embracing the new eating plan, even one so radically different from the way they were accustomed to eating.

“We focused mainly on the macronutrient makeup,” said Matthew Taylor, PhD, who supervised the diet study on a day-to-day basis. Instead of distributing a rigid diet plan, with prespecified meals and snacks, “We talked more in general about foods they could have and foods they couldn’t have.”

“When people think ‘ketogenic,’ they think bacon, eggs, oil, butter and cream, and may have an automatic negative connotation that this is unhealthy eating,” Dr. Taylor said in an interview. “But yes, eggs were in there and, because a lot of people really like bacon, there was bacon, too!”

The educational sessions did include teaching about healthy and unhealthy fats, and Dr. Taylor “tried to steer people toward the healthier ones, like olive oil, avocados, and nuts. But I didn’t say, ‘Eat this one and not that one.’ If it took melting butter on vegetables to get to that fat ratio, I was not as concerned about where the fat came from as about getting there and maintaining ketosis.”

KDRAFT also had a twist that’s becoming more common among ketogenic eating plans: lots of vegetables. Dr. Taylor asked participants to concentrate on nonstarchy vegetables and forgo potatoes, corn, beans, and lima beans, although some people did enjoy peas occasionally.

“We used to be think we had to restrict vegetables or people would go out of ketosis more easily. But that doesn’t seem to be true. We focused a lot on eating vegetables, and everyone increased their vegetable intake dramatically. We actually tried to use vegetables as a vehicle for fat. For example, people would roast Brussels sprouts or broccoli in olive oil and then put melted butter on it. It was pretty much, ‘Eat all the vegetables you can and put fat on them.’”

Fruits are full of sugar, so they are not liberally used in most ketogenic diets, but KDRAFT did allow one type: berries, and blueberries in particular. “We had people eating a couple of small handfuls of berries throughout the day and still being able to maintain ketosis. We did severely cut back on the amount and type of fruit people could have, but berries seemed to work well.”

Whipping cream had a place, too. “It fit really well in the diet, because it’s basically all fat,” Dr. Taylor said. “It’s used more often in pediatric ketogenic diets as a milk substitute. One thing our subjects liked to do was use it to make a sweet snack. All it takes is a packet of [stevia] sweetener and some vanilla. Then you whip and freeze it and it’s like an ice cream dessert.”

After the initial drop-outs, the remaining study pairs embraced the intervention enthusiastically.

“When the study partner took the diet on too, we had our best success. One of our last pairs had an entire family join in – children, grandchildren, everyone decided to follow the diet. That is a very helpful piece to this. It’s difficult to always say, ‘Here’s our normal food and here’s the keto food over here.’”

The dropouts occurred very early. These study pairs, all of whom included patients with moderate Alzheimer’s, never embraced the plan at all, and this is a telling point, Dr. Taylor noted.

“When you get to a level of dementia there are so many other things in the caregiving process that taking on big behavioral changes is very difficult.”

Although the study showed that the diet wasn’t practical for sicker patients at home, it still might be beneficial in other settings, said Debra Sullivan, PhD, RD. Dr. Sullivan chairs the department of dietetics and nutrition at the University of Kansas Medical Center and holds the Midwest Dairy Council Endowed Professorship in Clinical Nutrition.

“I think that we might be able to create a version of the diet that could be used in an institutional setting for our more advanced patients,” she said. “But there’s no denying that this can be challenging. It’s a big change from the way the typical American eats.”

None of the KDRAFT participants experienced any lipid changes, for either better or worse. The 3-month intervention was long enough to have picked up such changes if they were in the offing, said principal investigator Russell Swerdlow, MD. While there are mixed data on ketogenic diets’ atherogenic effects, many people respond positively, with improved cholesterol.

“Much of what it comes down to is, are you in a catabolic or anabolic states? Are you building up or tearing down? Excessive cholesterol is a sign of being overfed and laying down energy supplies. You take in carbon and turn it into cholesterol. But if you can trick your body into a catabolic state – essentially make it think it’s starving, which a ketogenic diet does – then you have consistently low insulin levels, and you don’t turn on the cholesterol synthesis pathway. You may increase your cholesterol intake through diet, but you’re not synthesizing it in your body, and that synthesis is what really drives your cholesterol level. If you’re not overeating, your body’s production goes down.”

Brain Energy and Memory (BEAM) study

Dr. Swerdlow isn’t the only clinician researcher looking at how a ketogenic diet might influence cognition. Suzanne Craft, PhD, well known for her investigations of the role of insulin signaling and therapy in AD, is running a ketogenic diet trial as well.

As noted on clinicaltrials.gov, the 24-week Brain Energy and Memory (BEAM) study aimed to recruit 25 subjects in two cohorts: adults with mild memory complaints, and cognitively normal adults with prediabetes. A comparator group of healthy controls will contribute cognitive assessments, blood and stool sample collection, neuroimaging, and lumbar puncture at baseline.

Both active groups will be randomized to 6 weeks of either a low-fat, high-carbohydrate diet, with carbs making up 50%-60% of daily caloric intake, or a modified ketogenic-Mediterranean Diet with carbs comprising less than 10% of daily caloric intake.

BEAM’s primary outcome will be changes in the AD cerebrospinal fluid biomarkers beta-amyloid and tau. Secondary endpoints include cognitive assessments, brain ketone uptake on PET scanning, and insulin sensitivity.

Dr. Cunnane has no financial interest in the MCT emulsion, which was supplied by Abitec. He reported conference travel support from Abitec, Nisshin OilliO, and Pruvit. He also reported receiving research project funding from Nestlé and Bulletproof.

Dr. Swerdlow had no financial disclosures.

[email protected]

On Twitter @alz_gal

LONDON – A 3-month diet comprised of 70% fat improved cognition in Alzheimer’s disease patients better than any anti-amyloid drug that has ever been tested.

In a small pilot study, Alzheimer’s patients who followed the University of Kansas’s ketogenic diet program improved an average of 4 points on one of the most important cognitive assessments in dementia care, the Alzheimer’s Disease Assessment Scale–cognitive domain (ADAS-cog). Not only was this gain statistically significant, but it reached a level that clinical trialists believe to be clinically meaningful, and it was similar to the gains that won Food and Drug Administration approval for donepezil in 1996, according to Russell Swerdlow, MD, director of the University of Kansas Alzheimer’s Disease Center in Fairway.

Diet and dementia

Emerging evidence suggests that modifying diet can help prevent Alzheimer’s and may even help AD patients think and function better. But this research has largely focused on the heart-healthy diets already proven successful in preventing and treating hypertension, diabetes, and cardiovascular disease. Most notably, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet cut the risk of AD by up to 53% (Alzheimers Dement. 2015 Sep;11[9]:1007-14) and also slowed aging-related cognitive decline (Alzheimers Dement. 2015 Sep; 11[9]:1015-22).

MIND is a combination of the low-salt, plant-focused DASH diet, and the heart-healthy Mediterranean diet. It is a moderate-fat plan, with a ratio of 33% fat, 38% carbohydrates, and 26% protein. Ideally, only 3% of the fat should be saturated, so MIND draws on olive oil, nuts, and other foods with monounsaturated fats, largely eschewing animal fats. It’s generally considered fairly easy to follow, since it allows a wide variety of whole grains, beans, nuts, fruits, vegetables, salads, fish, and poultry. Butter, red meat, fried foods, full-fat dairy, and fast foods are strict no-nos.

A ketogenic diet, however, turns MIND on its head. With a 70% fat, 20% protein, 10% carbohydrate ratio, a typical ketogenic diet nearly eliminates most fruits, and virtually all starchy vegetables, beans, and grains. It does, however, incorporate a large amount of fat from many sources, including olive oil, butter, cream, eggs, nuts, all kinds of meat, and fish. For a ketogenic diet, Dr. Swerdlow said, the ratio of fat to protein and carbs is more critical than the source of the fat.

MIND was designed to prevent the cardiovascular and endocrine disorders than predispose to dementia over the long term. But a ketogenic diet for patients with Alzheimer’s acutely manipulates the brain’s energy metabolism system, forcing it to use ketone bodies instead of glucose for fuel.

In normal energy metabolism, carbohydrates provide a ready supply of glucose, the brain’s primary fuel. When carbs are limited or absent, serum insulin decreases and glucagon increases. This promotes lipolysis. Ketones (primarily beta-hydroxybutyrate and acetoacetate) are formed in the liver from the newly released fatty acids, and released into the circulation, including into the brain during times of decreased glucose availability – a state characteristic of Alzheimer’s disease.

Induced ketogenesis trial

Inducing ketosis through diet seems to help correct the normal, age-related decline in the brain’s ability to use glucose, said Stephen Cunnane, PhD, who also presented ketogenic intervention results at AAIC. “Cognitively normal, healthy older adults experience a 10% reduction in the brain’s ability to metabolize glucose compared to healthy young people,” he said in an interview. But this decline accelerates as Alzheimer’s hits. Those with early AD have a 20% decrement in glucose utilization, compared with healthy elders.

Details of the KDRAFT study

The BENEFIC study looked only at the effects of an MCT supplement, which may not deliver all the metabolic benefits of a ketogenic diet. KDRAFT, however, employed both, and assessed not only cognitive outcomes and adverse effects, but the practical matter of whether AD patients and their caregivers could implement the diet and stick to it.

Couples recruited into the trial met with a dietitian who explained the importance of sticking with the strict fat:carb:protein ratio. It’s not easy to stay in that zone, Dr. Swerdlow said, and the MCT supplement really helps there.

“Adding the MCT, which is typically done for the ketogenic diet in epilepsy, increases the fat intake so you can tolerate a bit more carbohydrate and still remain in ketosis. MCT therefore makes it easier to successfully do the diet, if we define success by time in ketosis. Ultimately, it is an iterative diet. You check your urine, and if you are in ketosis, you are doing well. If you are not in ketosis, you have to increase your fat intake, decrease your carb intake, or both.”

The study comprised 15 patients (7 with very mild AD, 4 with mild, and 4 with moderate disease). All patients were instructed to remain on their current medications for Alzheimer’s disease for the duration of the study if they were taking any. All of the patients with moderate AD and one with very mild AD dropped out of the study within the first month, citing caregiver burden. The supplement was in the form of an oil, not an emulsion like the BENEFIC supplement, and it caused diarrhea and nausea in five subjects, although none discontinued because of that.

“We found that a slow titration of the oil could deal with the GI issues. Rather, the primary deal-breaker seemed to be the stress of planning the menus and preparing the meals.”

One patient discontinued his cholinesterase inhibitor during the study, for unknown reasons. His cognitive scores declined, but was still included in the diet-compliant analysis.

The diet didn’t affect weight, blood pressure, insulin sensitivity or resistance, or glucose level, but the intervention was short-lived. Nor were there any significant changes in high-density, low-density, or total cholesterol. Liver enzymes were stable, too.

“The only thing that changed was that they really did increase their fat and decrease their carb intake,” Dr. Swerdlow said. Daily fat jumped from 91 g to 167 g, and carbs dropped from 201 g to 46 g.

Almost everyone who stuck with the diet achieved and maintained ketosis during the study, although with varying degrees of success. “Many only had a trace amount of urinary ketones,” Dr. Swerdlow said. The investigators tracked serum beta hydroxybutyrate levels every month as well, and those measures also confirmed ketosis in the group as a whole, although some patients fluctuated in and out of the state.

The cognitive changes were striking, he said. In the 10-patient analysis, ADAS-cog scores improved by an average of 4.1 points. The results were better when Dr. Swerdlow excluded the patient who stopped his cholinesterase inhibitor medication. In that nine-patient group, the ADAS-cog improved an average of 5.3 points.

While urging caution over the small sample size and lack of a control comparator, Dr. Swerdlow expressed deep satisfaction over the outcomes. A clinician as well as a researcher, he is accustomed to the slow but inexorable decline of AD patients.

“I’m going to try to relate the impression you get in the clinic with these scores,” he said. “Very rarely, but sometimes, with a cholinesterase inhibitor in patients, we’ll see something like a 7-point change. That’s a fantastic response, an improvement you can see across the room. A change of 2 points really doesn’t look that much different, although caregivers will tell you there is a subtle change, maybe a little more focus. The average we got in our 10 subjects was a 4-point improvement. That’s impressive. And a 5-point change is like rolling the clock back by a year.”

The improvements didn’t last, though. A 1-month washout period followed the intervention. By the end, both ADAS-cog and Mini-Mental State Examination scores had returned to their baseline levels. At the end of the study, a few of the patients and their partners expressed their intent to resume the diet, but the investigators do not know whether this indeed happened. Still, the results are encouraging enough that, like Dr. Cunnane, Dr. Swerdlow hopes to conduct a larger, longer study – one that would include a control group.

Future investigations of the ketogenic diet in AD might do well to also include an exercise component, both researchers mentioned. In addition to starvation, ketogenic dieting, and MCT supplementation, exercise is an effective way to induce ketogenesis.

“Exercise produces ketones, but most importantly, it increases the capacity of the brain to use ketones,” Dr. Cunnane said. The connection may help explain some of the cognitive benefits seen in exercise trials in patients with MCI and AD.

“This raises the possibility that if in fact exercise benefits the brain, ketone bodies may mediate some of that effect,” Dr. Swerdlow said. “Could exercise potentiate the ketosis from the diet? That is possible, and maybe using these interventions in conjunction would be synergistic. At this point, we are just happy to show the diet is feasible, if even for a limited period.”

Implementing KDRAFT: Research team dishes the skinny on fats

The KDRAFT study diet is surprisingly flexible despite its strict ratio of fat to protein and carbohydrate, according to the University of Kansas research team that implemented it. It only took a few counseling sessions to get most study participants enthusiastically embracing the new eating plan, even one so radically different from the way they were accustomed to eating.

“We focused mainly on the macronutrient makeup,” said Matthew Taylor, PhD, who supervised the diet study on a day-to-day basis. Instead of distributing a rigid diet plan, with prespecified meals and snacks, “We talked more in general about foods they could have and foods they couldn’t have.”

“When people think ‘ketogenic,’ they think bacon, eggs, oil, butter and cream, and may have an automatic negative connotation that this is unhealthy eating,” Dr. Taylor said in an interview. “But yes, eggs were in there and, because a lot of people really like bacon, there was bacon, too!”

The educational sessions did include teaching about healthy and unhealthy fats, and Dr. Taylor “tried to steer people toward the healthier ones, like olive oil, avocados, and nuts. But I didn’t say, ‘Eat this one and not that one.’ If it took melting butter on vegetables to get to that fat ratio, I was not as concerned about where the fat came from as about getting there and maintaining ketosis.”

KDRAFT also had a twist that’s becoming more common among ketogenic eating plans: lots of vegetables. Dr. Taylor asked participants to concentrate on nonstarchy vegetables and forgo potatoes, corn, beans, and lima beans, although some people did enjoy peas occasionally.

“We used to be think we had to restrict vegetables or people would go out of ketosis more easily. But that doesn’t seem to be true. We focused a lot on eating vegetables, and everyone increased their vegetable intake dramatically. We actually tried to use vegetables as a vehicle for fat. For example, people would roast Brussels sprouts or broccoli in olive oil and then put melted butter on it. It was pretty much, ‘Eat all the vegetables you can and put fat on them.’”

Fruits are full of sugar, so they are not liberally used in most ketogenic diets, but KDRAFT did allow one type: berries, and blueberries in particular. “We had people eating a couple of small handfuls of berries throughout the day and still being able to maintain ketosis. We did severely cut back on the amount and type of fruit people could have, but berries seemed to work well.”

Whipping cream had a place, too. “It fit really well in the diet, because it’s basically all fat,” Dr. Taylor said. “It’s used more often in pediatric ketogenic diets as a milk substitute. One thing our subjects liked to do was use it to make a sweet snack. All it takes is a packet of [stevia] sweetener and some vanilla. Then you whip and freeze it and it’s like an ice cream dessert.”

After the initial drop-outs, the remaining study pairs embraced the intervention enthusiastically.

“When the study partner took the diet on too, we had our best success. One of our last pairs had an entire family join in – children, grandchildren, everyone decided to follow the diet. That is a very helpful piece to this. It’s difficult to always say, ‘Here’s our normal food and here’s the keto food over here.’”

The dropouts occurred very early. These study pairs, all of whom included patients with moderate Alzheimer’s, never embraced the plan at all, and this is a telling point, Dr. Taylor noted.

“When you get to a level of dementia there are so many other things in the caregiving process that taking on big behavioral changes is very difficult.”

Although the study showed that the diet wasn’t practical for sicker patients at home, it still might be beneficial in other settings, said Debra Sullivan, PhD, RD. Dr. Sullivan chairs the department of dietetics and nutrition at the University of Kansas Medical Center and holds the Midwest Dairy Council Endowed Professorship in Clinical Nutrition.

“I think that we might be able to create a version of the diet that could be used in an institutional setting for our more advanced patients,” she said. “But there’s no denying that this can be challenging. It’s a big change from the way the typical American eats.”

None of the KDRAFT participants experienced any lipid changes, for either better or worse. The 3-month intervention was long enough to have picked up such changes if they were in the offing, said principal investigator Russell Swerdlow, MD. While there are mixed data on ketogenic diets’ atherogenic effects, many people respond positively, with improved cholesterol.

“Much of what it comes down to is, are you in a catabolic or anabolic states? Are you building up or tearing down? Excessive cholesterol is a sign of being overfed and laying down energy supplies. You take in carbon and turn it into cholesterol. But if you can trick your body into a catabolic state – essentially make it think it’s starving, which a ketogenic diet does – then you have consistently low insulin levels, and you don’t turn on the cholesterol synthesis pathway. You may increase your cholesterol intake through diet, but you’re not synthesizing it in your body, and that synthesis is what really drives your cholesterol level. If you’re not overeating, your body’s production goes down.”

Brain Energy and Memory (BEAM) study

Dr. Swerdlow isn’t the only clinician researcher looking at how a ketogenic diet might influence cognition. Suzanne Craft, PhD, well known for her investigations of the role of insulin signaling and therapy in AD, is running a ketogenic diet trial as well.

As noted on clinicaltrials.gov, the 24-week Brain Energy and Memory (BEAM) study aimed to recruit 25 subjects in two cohorts: adults with mild memory complaints, and cognitively normal adults with prediabetes. A comparator group of healthy controls will contribute cognitive assessments, blood and stool sample collection, neuroimaging, and lumbar puncture at baseline.

Both active groups will be randomized to 6 weeks of either a low-fat, high-carbohydrate diet, with carbs making up 50%-60% of daily caloric intake, or a modified ketogenic-Mediterranean Diet with carbs comprising less than 10% of daily caloric intake.

BEAM’s primary outcome will be changes in the AD cerebrospinal fluid biomarkers beta-amyloid and tau. Secondary endpoints include cognitive assessments, brain ketone uptake on PET scanning, and insulin sensitivity.

Dr. Cunnane has no financial interest in the MCT emulsion, which was supplied by Abitec. He reported conference travel support from Abitec, Nisshin OilliO, and Pruvit. He also reported receiving research project funding from Nestlé and Bulletproof.

Dr. Swerdlow had no financial disclosures.

[email protected]

On Twitter @alz_gal

LONDON – A 3-month diet comprised of 70% fat improved cognition in Alzheimer’s disease patients better than any anti-amyloid drug that has ever been tested.

In a small pilot study, Alzheimer’s patients who followed the University of Kansas’s ketogenic diet program improved an average of 4 points on one of the most important cognitive assessments in dementia care, the Alzheimer’s Disease Assessment Scale–cognitive domain (ADAS-cog). Not only was this gain statistically significant, but it reached a level that clinical trialists believe to be clinically meaningful, and it was similar to the gains that won Food and Drug Administration approval for donepezil in 1996, according to Russell Swerdlow, MD, director of the University of Kansas Alzheimer’s Disease Center in Fairway.

Diet and dementia

Emerging evidence suggests that modifying diet can help prevent Alzheimer’s and may even help AD patients think and function better. But this research has largely focused on the heart-healthy diets already proven successful in preventing and treating hypertension, diabetes, and cardiovascular disease. Most notably, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet cut the risk of AD by up to 53% (Alzheimers Dement. 2015 Sep;11[9]:1007-14) and also slowed aging-related cognitive decline (Alzheimers Dement. 2015 Sep; 11[9]:1015-22).

MIND is a combination of the low-salt, plant-focused DASH diet, and the heart-healthy Mediterranean diet. It is a moderate-fat plan, with a ratio of 33% fat, 38% carbohydrates, and 26% protein. Ideally, only 3% of the fat should be saturated, so MIND draws on olive oil, nuts, and other foods with monounsaturated fats, largely eschewing animal fats. It’s generally considered fairly easy to follow, since it allows a wide variety of whole grains, beans, nuts, fruits, vegetables, salads, fish, and poultry. Butter, red meat, fried foods, full-fat dairy, and fast foods are strict no-nos.

A ketogenic diet, however, turns MIND on its head. With a 70% fat, 20% protein, 10% carbohydrate ratio, a typical ketogenic diet nearly eliminates most fruits, and virtually all starchy vegetables, beans, and grains. It does, however, incorporate a large amount of fat from many sources, including olive oil, butter, cream, eggs, nuts, all kinds of meat, and fish. For a ketogenic diet, Dr. Swerdlow said, the ratio of fat to protein and carbs is more critical than the source of the fat.

MIND was designed to prevent the cardiovascular and endocrine disorders than predispose to dementia over the long term. But a ketogenic diet for patients with Alzheimer’s acutely manipulates the brain’s energy metabolism system, forcing it to use ketone bodies instead of glucose for fuel.

In normal energy metabolism, carbohydrates provide a ready supply of glucose, the brain’s primary fuel. When carbs are limited or absent, serum insulin decreases and glucagon increases. This promotes lipolysis. Ketones (primarily beta-hydroxybutyrate and acetoacetate) are formed in the liver from the newly released fatty acids, and released into the circulation, including into the brain during times of decreased glucose availability – a state characteristic of Alzheimer’s disease.

Induced ketogenesis trial

Inducing ketosis through diet seems to help correct the normal, age-related decline in the brain’s ability to use glucose, said Stephen Cunnane, PhD, who also presented ketogenic intervention results at AAIC. “Cognitively normal, healthy older adults experience a 10% reduction in the brain’s ability to metabolize glucose compared to healthy young people,” he said in an interview. But this decline accelerates as Alzheimer’s hits. Those with early AD have a 20% decrement in glucose utilization, compared with healthy elders.

Details of the KDRAFT study

The BENEFIC study looked only at the effects of an MCT supplement, which may not deliver all the metabolic benefits of a ketogenic diet. KDRAFT, however, employed both, and assessed not only cognitive outcomes and adverse effects, but the practical matter of whether AD patients and their caregivers could implement the diet and stick to it.

Couples recruited into the trial met with a dietitian who explained the importance of sticking with the strict fat:carb:protein ratio. It’s not easy to stay in that zone, Dr. Swerdlow said, and the MCT supplement really helps there.

“Adding the MCT, which is typically done for the ketogenic diet in epilepsy, increases the fat intake so you can tolerate a bit more carbohydrate and still remain in ketosis. MCT therefore makes it easier to successfully do the diet, if we define success by time in ketosis. Ultimately, it is an iterative diet. You check your urine, and if you are in ketosis, you are doing well. If you are not in ketosis, you have to increase your fat intake, decrease your carb intake, or both.”

The study comprised 15 patients (7 with very mild AD, 4 with mild, and 4 with moderate disease). All patients were instructed to remain on their current medications for Alzheimer’s disease for the duration of the study if they were taking any. All of the patients with moderate AD and one with very mild AD dropped out of the study within the first month, citing caregiver burden. The supplement was in the form of an oil, not an emulsion like the BENEFIC supplement, and it caused diarrhea and nausea in five subjects, although none discontinued because of that.

“We found that a slow titration of the oil could deal with the GI issues. Rather, the primary deal-breaker seemed to be the stress of planning the menus and preparing the meals.”

One patient discontinued his cholinesterase inhibitor during the study, for unknown reasons. His cognitive scores declined, but was still included in the diet-compliant analysis.

The diet didn’t affect weight, blood pressure, insulin sensitivity or resistance, or glucose level, but the intervention was short-lived. Nor were there any significant changes in high-density, low-density, or total cholesterol. Liver enzymes were stable, too.

“The only thing that changed was that they really did increase their fat and decrease their carb intake,” Dr. Swerdlow said. Daily fat jumped from 91 g to 167 g, and carbs dropped from 201 g to 46 g.

Almost everyone who stuck with the diet achieved and maintained ketosis during the study, although with varying degrees of success. “Many only had a trace amount of urinary ketones,” Dr. Swerdlow said. The investigators tracked serum beta hydroxybutyrate levels every month as well, and those measures also confirmed ketosis in the group as a whole, although some patients fluctuated in and out of the state.

The cognitive changes were striking, he said. In the 10-patient analysis, ADAS-cog scores improved by an average of 4.1 points. The results were better when Dr. Swerdlow excluded the patient who stopped his cholinesterase inhibitor medication. In that nine-patient group, the ADAS-cog improved an average of 5.3 points.

While urging caution over the small sample size and lack of a control comparator, Dr. Swerdlow expressed deep satisfaction over the outcomes. A clinician as well as a researcher, he is accustomed to the slow but inexorable decline of AD patients.

“I’m going to try to relate the impression you get in the clinic with these scores,” he said. “Very rarely, but sometimes, with a cholinesterase inhibitor in patients, we’ll see something like a 7-point change. That’s a fantastic response, an improvement you can see across the room. A change of 2 points really doesn’t look that much different, although caregivers will tell you there is a subtle change, maybe a little more focus. The average we got in our 10 subjects was a 4-point improvement. That’s impressive. And a 5-point change is like rolling the clock back by a year.”

The improvements didn’t last, though. A 1-month washout period followed the intervention. By the end, both ADAS-cog and Mini-Mental State Examination scores had returned to their baseline levels. At the end of the study, a few of the patients and their partners expressed their intent to resume the diet, but the investigators do not know whether this indeed happened. Still, the results are encouraging enough that, like Dr. Cunnane, Dr. Swerdlow hopes to conduct a larger, longer study – one that would include a control group.

Future investigations of the ketogenic diet in AD might do well to also include an exercise component, both researchers mentioned. In addition to starvation, ketogenic dieting, and MCT supplementation, exercise is an effective way to induce ketogenesis.

“Exercise produces ketones, but most importantly, it increases the capacity of the brain to use ketones,” Dr. Cunnane said. The connection may help explain some of the cognitive benefits seen in exercise trials in patients with MCI and AD.

“This raises the possibility that if in fact exercise benefits the brain, ketone bodies may mediate some of that effect,” Dr. Swerdlow said. “Could exercise potentiate the ketosis from the diet? That is possible, and maybe using these interventions in conjunction would be synergistic. At this point, we are just happy to show the diet is feasible, if even for a limited period.”

Implementing KDRAFT: Research team dishes the skinny on fats

The KDRAFT study diet is surprisingly flexible despite its strict ratio of fat to protein and carbohydrate, according to the University of Kansas research team that implemented it. It only took a few counseling sessions to get most study participants enthusiastically embracing the new eating plan, even one so radically different from the way they were accustomed to eating.

“We focused mainly on the macronutrient makeup,” said Matthew Taylor, PhD, who supervised the diet study on a day-to-day basis. Instead of distributing a rigid diet plan, with prespecified meals and snacks, “We talked more in general about foods they could have and foods they couldn’t have.”

“When people think ‘ketogenic,’ they think bacon, eggs, oil, butter and cream, and may have an automatic negative connotation that this is unhealthy eating,” Dr. Taylor said in an interview. “But yes, eggs were in there and, because a lot of people really like bacon, there was bacon, too!”

The educational sessions did include teaching about healthy and unhealthy fats, and Dr. Taylor “tried to steer people toward the healthier ones, like olive oil, avocados, and nuts. But I didn’t say, ‘Eat this one and not that one.’ If it took melting butter on vegetables to get to that fat ratio, I was not as concerned about where the fat came from as about getting there and maintaining ketosis.”

KDRAFT also had a twist that’s becoming more common among ketogenic eating plans: lots of vegetables. Dr. Taylor asked participants to concentrate on nonstarchy vegetables and forgo potatoes, corn, beans, and lima beans, although some people did enjoy peas occasionally.

“We used to be think we had to restrict vegetables or people would go out of ketosis more easily. But that doesn’t seem to be true. We focused a lot on eating vegetables, and everyone increased their vegetable intake dramatically. We actually tried to use vegetables as a vehicle for fat. For example, people would roast Brussels sprouts or broccoli in olive oil and then put melted butter on it. It was pretty much, ‘Eat all the vegetables you can and put fat on them.’”

Fruits are full of sugar, so they are not liberally used in most ketogenic diets, but KDRAFT did allow one type: berries, and blueberries in particular. “We had people eating a couple of small handfuls of berries throughout the day and still being able to maintain ketosis. We did severely cut back on the amount and type of fruit people could have, but berries seemed to work well.”

Whipping cream had a place, too. “It fit really well in the diet, because it’s basically all fat,” Dr. Taylor said. “It’s used more often in pediatric ketogenic diets as a milk substitute. One thing our subjects liked to do was use it to make a sweet snack. All it takes is a packet of [stevia] sweetener and some vanilla. Then you whip and freeze it and it’s like an ice cream dessert.”

After the initial drop-outs, the remaining study pairs embraced the intervention enthusiastically.

“When the study partner took the diet on too, we had our best success. One of our last pairs had an entire family join in – children, grandchildren, everyone decided to follow the diet. That is a very helpful piece to this. It’s difficult to always say, ‘Here’s our normal food and here’s the keto food over here.’”

The dropouts occurred very early. These study pairs, all of whom included patients with moderate Alzheimer’s, never embraced the plan at all, and this is a telling point, Dr. Taylor noted.

“When you get to a level of dementia there are so many other things in the caregiving process that taking on big behavioral changes is very difficult.”

Although the study showed that the diet wasn’t practical for sicker patients at home, it still might be beneficial in other settings, said Debra Sullivan, PhD, RD. Dr. Sullivan chairs the department of dietetics and nutrition at the University of Kansas Medical Center and holds the Midwest Dairy Council Endowed Professorship in Clinical Nutrition.

“I think that we might be able to create a version of the diet that could be used in an institutional setting for our more advanced patients,” she said. “But there’s no denying that this can be challenging. It’s a big change from the way the typical American eats.”

None of the KDRAFT participants experienced any lipid changes, for either better or worse. The 3-month intervention was long enough to have picked up such changes if they were in the offing, said principal investigator Russell Swerdlow, MD. While there are mixed data on ketogenic diets’ atherogenic effects, many people respond positively, with improved cholesterol.

“Much of what it comes down to is, are you in a catabolic or anabolic states? Are you building up or tearing down? Excessive cholesterol is a sign of being overfed and laying down energy supplies. You take in carbon and turn it into cholesterol. But if you can trick your body into a catabolic state – essentially make it think it’s starving, which a ketogenic diet does – then you have consistently low insulin levels, and you don’t turn on the cholesterol synthesis pathway. You may increase your cholesterol intake through diet, but you’re not synthesizing it in your body, and that synthesis is what really drives your cholesterol level. If you’re not overeating, your body’s production goes down.”

Brain Energy and Memory (BEAM) study

Dr. Swerdlow isn’t the only clinician researcher looking at how a ketogenic diet might influence cognition. Suzanne Craft, PhD, well known for her investigations of the role of insulin signaling and therapy in AD, is running a ketogenic diet trial as well.

As noted on clinicaltrials.gov, the 24-week Brain Energy and Memory (BEAM) study aimed to recruit 25 subjects in two cohorts: adults with mild memory complaints, and cognitively normal adults with prediabetes. A comparator group of healthy controls will contribute cognitive assessments, blood and stool sample collection, neuroimaging, and lumbar puncture at baseline.

Both active groups will be randomized to 6 weeks of either a low-fat, high-carbohydrate diet, with carbs making up 50%-60% of daily caloric intake, or a modified ketogenic-Mediterranean Diet with carbs comprising less than 10% of daily caloric intake.

BEAM’s primary outcome will be changes in the AD cerebrospinal fluid biomarkers beta-amyloid and tau. Secondary endpoints include cognitive assessments, brain ketone uptake on PET scanning, and insulin sensitivity.

Dr. Cunnane has no financial interest in the MCT emulsion, which was supplied by Abitec. He reported conference travel support from Abitec, Nisshin OilliO, and Pruvit. He also reported receiving research project funding from Nestlé and Bulletproof.

Dr. Swerdlow had no financial disclosures.

[email protected]

On Twitter @alz_gal

CHICAGO – If severe eczema persists in a pediatric patient despite your best treatment efforts, think allergic contact dermatitis.

“Or, if your eczema patients tell you that they have a cream that’s making things worse, you should think about a contact allergen,” Catalina Matiz, MD, said at the World Congress of Pediatric Dermatology.

Allergic contact dermatitis (ACD) is a type IV delayed-type hypersensitivity reaction to haptens that come into contact with the skin. Poison ivy is a common plant-based culprit, while nickel is the most common metal allergen in adults and children. “The skin barrier also plays a role,” said Dr. Matiz of the department of dermatology at Rady Children’s Hospital–San Diego, and the University of California, San Diego. “Compared with adults, children have a thinner stratum corneum, and some haptens can penetrate the skin. Some studies suggest that patients with atopic dermatitis may have increased rates of allergic sensitization, and filaggrin mutations have been found in patients with atopic dermatitis and in patients with ACD to nickel. Filaggrin helps to aggregate the cytoskeletal proteins that form the cornified cell envelope. Without filaggrin, the skin barrier is defective.”

[email protected]

CHICAGO – If severe eczema persists in a pediatric patient despite your best treatment efforts, think allergic contact dermatitis.

“Or, if your eczema patients tell you that they have a cream that’s making things worse, you should think about a contact allergen,” Catalina Matiz, MD, said at the World Congress of Pediatric Dermatology.

Allergic contact dermatitis (ACD) is a type IV delayed-type hypersensitivity reaction to haptens that come into contact with the skin. Poison ivy is a common plant-based culprit, while nickel is the most common metal allergen in adults and children. “The skin barrier also plays a role,” said Dr. Matiz of the department of dermatology at Rady Children’s Hospital–San Diego, and the University of California, San Diego. “Compared with adults, children have a thinner stratum corneum, and some haptens can penetrate the skin. Some studies suggest that patients with atopic dermatitis may have increased rates of allergic sensitization, and filaggrin mutations have been found in patients with atopic dermatitis and in patients with ACD to nickel. Filaggrin helps to aggregate the cytoskeletal proteins that form the cornified cell envelope. Without filaggrin, the skin barrier is defective.”

[email protected]

CHICAGO – If severe eczema persists in a pediatric patient despite your best treatment efforts, think allergic contact dermatitis.

“Or, if your eczema patients tell you that they have a cream that’s making things worse, you should think about a contact allergen,” Catalina Matiz, MD, said at the World Congress of Pediatric Dermatology.

Allergic contact dermatitis (ACD) is a type IV delayed-type hypersensitivity reaction to haptens that come into contact with the skin. Poison ivy is a common plant-based culprit, while nickel is the most common metal allergen in adults and children. “The skin barrier also plays a role,” said Dr. Matiz of the department of dermatology at Rady Children’s Hospital–San Diego, and the University of California, San Diego. “Compared with adults, children have a thinner stratum corneum, and some haptens can penetrate the skin. Some studies suggest that patients with atopic dermatitis may have increased rates of allergic sensitization, and filaggrin mutations have been found in patients with atopic dermatitis and in patients with ACD to nickel. Filaggrin helps to aggregate the cytoskeletal proteins that form the cornified cell envelope. Without filaggrin, the skin barrier is defective.”

[email protected]