‘Chemo Brain’ May Have Targetable Causes

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.

BOSTON – The risk for cognitive decline following cancer treatment varies by both cancer and therapy types, and can range from subtle changes to severe deficits, according to a researcher.

Patients who are older, have lower cognitive reserves, or have comorbidities such as cardiovascular disease or diabetes are at risk for cognitive problems following cancer treatment, said Tim A. Ahles, Ph.D., director of the Neurocognitive Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York.

“I think it’s important that we identify these modifiable risk factors for intervention, and some of the nonmodifiable risk factors that inform decision making,” he said at the Palliative Care in Oncology Symposium.

“When we talk about cognitive function, we’re really talking about how does cancer and cancer treatment impact on memory, concentration, executive function, or ability to multitask, the speed at which we process information,” he said.

Oncologists have known for decades that brain tumors and their treatment have a negative effect on cognitive function, particularly among children under 5 years of age, whose developing brains are sensitive to treatments such as chemotherapy, surgery, radiation, and high-dose steroids.

There is also a dose-response effect, with high-dose chemotherapy such as ablative regimens used for bone-marrow transplantation being associated with higher probability of cognitive problems.

Dr. Ahles noted that about two-thirds of adult survivors of childhood cancers develop chronic illnesses within 30 years of diagnosis, including cardiac and pulmonary disease, and diabetes and endocrine dysfunction.

“It turns out they’re also at higher risk for cognitive issues,” including white matter abnormalities and microvascular stroke, he said.

The population of survivors of brain tumors and childhood cancers is dwarfed, however, by the large and growing population of breast, colorectal, lung, and prostate cancer patients who are diagnosed every year and exposed to adjuvant therapies, he added.

Aging and cognitive reserve

Evidence from breast cancer studies has shown that about 20%-25% of patients have lower than expected cognitive functioning – based on age, education, occupation, and other factors – before they embark on adjuvant therapy.

“That’s actually a risk factor for posttreatment cognitive decline, so there’s something that’s already going on that’s disrupting the cognitive information-processing system before we even start adjuvant treatment that may be critically important in terms of their outcomes as survivors,” Dr. Ahles said.

A significant subset of women in longitudinal studies of breast cancer survivors – about 15%-30% – experience long-term posttreatment cognitive problems, making it imperative for researchers and clinicians to identify risk factors for persistent cognitive decline, he said.

There is evidence to suggest that cancer treatments may interplay with biologic factors at the cellular level to increase the risk for cognitive loss. For example, aging is associated with reduction in brain volume, decrease in white matter integrity, and decreases in vascularization and neurotransmitter activity.

The effects of age on the brain are attenuated, however, among patients with higher cognitive reserves, defined as a combination of innate and developed cognitive capacity. Cognitive reserve is influenced by a number of factors, including genetics, education, occupational attainment, and lifestyle.

High cognitive reserve has been associated with later onset of Alzheimer’s disease symptoms and smaller changes in cognitive function with normal aging or following a brain injury, Dr. Ahles noted.

In a longitudinal study of cognitive changes associated with adjuvant therapy for breast cancer, Dr. Ahles and colleagues found that both age and pretreatment cognitive reserve were related to posttreatment decline in processing speed in women exposed to chemotherapy, compared with those who did not have chemotherapy or with healthy controls. In addition, chemotherapy had a short-term impact on verbal ability. The authors found evidence to suggest the patterns they saw may be related to the combination of chemotherapy and tamoxifen.

Part of the difficulty of studying cognitive decline among older patients is the higher prevalence of changes associated with aging. Dr. Ahles pointed to a French longitudinal study of women over 65 being treated for breast cancer, in which investigators found that 41% of the study population had cognitive impairment before starting on adjuvant therapy.

Older adults may be more frail, with diminished biological reserves and lower resistance to stressors caused by “cumulative declines across a variety of physiological systems making you more vulnerable to adverse events,” Dr. Ahles said.

Aging and genetics

Genes associated with cognitive aging are also risk factors for posttreatment cognitive decline, notably the genetic variants of APOE, including the epsilon 4 (APOE-e4) allele linked to increased risk for early-onset Alzheimer’s disease.

Dr. Ahles and colleagues had previously shown that APOE-e4 may be a biomarker for increased risk for chemotherapy-induced cognitive decline. The adverse effects of APOE-e4 appear to be mitigated somewhat by smoking, because it may correct for a deficit in nicotinic receptor density and dopamine levels in carriers.

Another genetic factor linked to postchemotherapy cognitive decline is the Val158Met polymorphism of the gene encoding for Catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine. Patients with this polymorphism have rapid dopamine metabolism, resulting in reduced dopamine activity.

These findings point to potential molecular mechanisms for cognitive changes associated with chemotherapy, and suggest that therapies targeted at neurotransmitter systems may ameliorate the effect, Dr. Ahles said.

He noted that animal studies have shown that fluoxetine (Prozac) prevents deficits in behavior and hippocampal function associated with 5-fluourauracil (5-FU), and that nicotine patches have been shown to improve cognitive functioning in patients with mild cognitive impairment.

The symposium was cosponsored by AAHPM, ASCO, ASTRO, and MASCC.