Neuroscience

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Posts tagged cognitive decline

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A New Window of Opportunity to Prevent Cardiovascular and Cerebrovascular Diseases

Future prevention and treatment strategies for vascular diseases may lie in the evaluation of early brain imaging tests long before heart attacks or strokes occur, according to a systematic review conducted by a team of cardiologists, neuroscientists, and psychiatrists from Icahn School of Medicine at Mount Sinai and published in the October issue of JACC Cardiovascular Imaging.

For the review, Mount Sinai researchers examined all relevant brain imaging studies conducted over the last 33 years. They looked at studies that used every available brain imaging modality in patients with vascular disease risk factors but no symptoms that would lead to a diagnosis of diseased blood vessels (vascular disease) in the  heart or brain, or periphery (e.g. arms and legs).

The review demonstrates that patients with high blood pressure, diabetes, obesity, high cholesterol, smoking, or metabolic syndrome, but no symptoms, still had visible signs on their neuroimaging scans of structural and functional brain changes long before the development of any events related to vascular diseases of the heart (heart attack) or brain (stroke).

"This is the first time we have been able to disentangle the brain effects of vascular disease risk factors from the brain effects of cardiovascular and cerebrovascular disease and/or events after they develop," says the article’s lead author, Joseph I. Friedman, MD, Associate Professor in the Departments of Psychiatry and Neuroscience at Icahn School of Medicine at Mount Sinai. "Moreover, subtle cognitive impairment is an important clinical manifestation of these vascular disease risk factor-related brain imaging changes in these otherwise healthy persons."

Dr. Friedman added that, because diminished cognitive capacity adversely impacts a person’s ability to benefit from treatment for these medical conditions, early identification of these brain changes may “present a new window of opportunity” for doctors to intervene early and improve prevention of advancement from vascular disease risk factors to established cardiovascular and cerebrovascular diseases. His team is currently testing these hypotheses in ongoing studies at Mount Sinai.

"Patients need to start today to control their vascular risk factors, otherwise their brains may forever harbor physical changes leading to devastating heart and vascular conditions impacting their future overall health and even cognitive decline causing diseases like dementia or when it exists it can accelerate Alzheimer’s," says study author, Valentin Fuster, MD, PhD, Director of Mount Sinai Heart, Physician-in-Chief of The Mount Sinai Hospital, and Chief of the Division of Cardiology at Icahn School of Medicine at Mount Sinai. "Our publication raises the possibility that these early brain changes are major warning signs of what the future may hold for these asymptomatic patients. These high risk patients, along with their doctors, hold the power to modify their daily vascular risk factors to help halt the future course of the manifestation of their potentially looming cardiovascular diseases."

"We hope our publication serves as a primer for cardiologists and other doctors interpreting the early neuroimaging data of their patients who may be high risk for vascular disease," says senior article author Jagat Narula, MD, PhD, Director of Cardiovascular Imaging, Professor of Medicine and Philip J. and Harriet L. Goodhart Chair in Cardiology at Icahn School of Medicine at Mount Sinai. "These subtle brain changes are clues to us physicians that our patients need to start to lower their vascular risk factors always and way before symptoms or a cardiac or brain event happens. This simple step to lower vascular risk factors can have huge impacts on global prevention efforts of cardiovascular diseases."  

Researchers identified the following impact of key vascular risk factors on the structural and functional brain health of asymptomatic patients:

  • Hypertension is associated with globally appreciable brain volume reductions,
    connecting brain fiber abnormalities, reduced brain blood flow, and alterations in the normal pattern of synchronized brain activity between different regions.
  • Diabetes is associated with connecting brain fiber abnormalities, reduced brain blood flow, and alterations in the normal pattern of synchronized brain activity between different regions.
  • Obesity is associated with brain volume reductions, reduced brain blood flow and metabolism.
  • High total cholesterol and LDL cholesterol are associated with brain volume reductions, and connecting brain fiber abnormalities. In addition, high triglycerides is associated with reduced brain blood flow, and high total cholesterol is associated with reduced brain metabolism.
  • Smoking is associated with brain volume reductions, and alterations of the normal pattern of blood flow. In addition, it causes reduced MAO B (Monoamine Oxidase B) which metabolizes dopamine, the neurotransmitter chemical that controls the brain’s reward and pleasure zones.
  • Metabolic Syndrome is associated with a greater burden of silent brain infarcts (SBIs), visible only on MRI, which represents subclinical cerebrovascular disease. In addition, it is associated with connecting brain fiber abnormalities, and alterations in the normal pattern of synchronized brain activity between different regions.

(Source: mountsinai.org)

Filed under cerebral blood flow vascular diseases neuroimaging cognitive decline brain structure neuroscience science

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Exercise key to warding off dementia
EXERCISE is one of the best ways to protect against dementia in later life and the earlier you start, the greater the effect, research suggests.
Participating in intellectually stimulating leisure activities, paid work, volunteer work or study can also help protect against memory loss and reduce the risk of developing Alzheimer’s disease.
UWA adjunct clinical professor Nicola Lautenschlager, who led a review of strategies to delay cognitive decline, says there is a growing body of evidence that suggests exercise is beneficial for brain health.
"The knowledge we have so far basically makes it very clear that regular physical activity, even at an older age, can be very beneficial for protecting cognition," she says.
"Beyond that it’s also very effective for protecting or maintaining mental health, especially in relation to symptoms of depression or anxiety."
Prof Lautenschlager, who is based at the University of Melbourne, says older people who are well enough are advised to do 150 minutes of physical activity a week, such as going for walks.
"When it comes [to] brain health…it would be good if the walking speed isn’t very slow, so it shouldn’t be a stroll but rather what we call moderate pace," she says.
"Research has shown that the level of physical activity has to have a certain intensity so that the brain benefits."
Enjoyable hobbies key to brain health
Hobbies that keep the brain active, such as playing an instrument, going to concerts or joining a book club, can also be very helpful as long as it is an activity a person enjoys, Prof Lautenschlager says.
"The minute you prescribe an activity they hate doing…most likely the effect in terms of being beneficial for brain health is lost," she says.
"It produces so much stress in the body not wanting to do it that the stress is more harmful than the benefit of keeping the brain active."
Prof Lautenschlager says middle age is a crucial time for making lifestyle decisions that will determine a person’s health in later life.
"Usually we are talking about when you move into your 30s, definitely the 40s and also still the 50s," she says.
"Things like a high blood pressure or carrying too much weight, if you do that in these decades, it seems to harm the brain long-term in terms of how healthy a person is in their 70s or 80s."
Ideally people should aim for a healthy lifestyle from childhood but luckily research shows lifestyle changes still have an effect on brain health if a person is already old, Prof Lautenschlager says.
"Even programs…with seniors in their 70s and 80s can still make a difference," she says.
The research was published this month in the journal Maturitas.

Exercise key to warding off dementia

EXERCISE is one of the best ways to protect against dementia in later life and the earlier you start, the greater the effect, research suggests.

Participating in intellectually stimulating leisure activities, paid work, volunteer work or study can also help protect against memory loss and reduce the risk of developing Alzheimer’s disease.

UWA adjunct clinical professor Nicola Lautenschlager, who led a review of strategies to delay cognitive decline, says there is a growing body of evidence that suggests exercise is beneficial for brain health.

"The knowledge we have so far basically makes it very clear that regular physical activity, even at an older age, can be very beneficial for protecting cognition," she says.

"Beyond that it’s also very effective for protecting or maintaining mental health, especially in relation to symptoms of depression or anxiety."

Prof Lautenschlager, who is based at the University of Melbourne, says older people who are well enough are advised to do 150 minutes of physical activity a week, such as going for walks.

"When it comes [to] brain health…it would be good if the walking speed isn’t very slow, so it shouldn’t be a stroll but rather what we call moderate pace," she says.

"Research has shown that the level of physical activity has to have a certain intensity so that the brain benefits."

Enjoyable hobbies key to brain health

Hobbies that keep the brain active, such as playing an instrument, going to concerts or joining a book club, can also be very helpful as long as it is an activity a person enjoys, Prof Lautenschlager says.

"The minute you prescribe an activity they hate doing…most likely the effect in terms of being beneficial for brain health is lost," she says.

"It produces so much stress in the body not wanting to do it that the stress is more harmful than the benefit of keeping the brain active."

Prof Lautenschlager says middle age is a crucial time for making lifestyle decisions that will determine a person’s health in later life.

"Usually we are talking about when you move into your 30s, definitely the 40s and also still the 50s," she says.

"Things like a high blood pressure or carrying too much weight, if you do that in these decades, it seems to harm the brain long-term in terms of how healthy a person is in their 70s or 80s."

Ideally people should aim for a healthy lifestyle from childhood but luckily research shows lifestyle changes still have an effect on brain health if a person is already old, Prof Lautenschlager says.

"Even programs…with seniors in their 70s and 80s can still make a difference," she says.

The research was published this month in the journal Maturitas.

Filed under exercise aging dementia alzheimer's disease cognitive decline neuroscience science

131 notes

MRI Technique Detects Evidence of Cognitive Decline Before Symptoms Appear
A magnetic resonance imaging (MRI) technique can detect signs of cognitive decline in the brain even before symptoms appear, according to a new study published online in the journal Radiology. The technique has the potential to serve as a biomarker in very early diagnosis of preclinical dementia.
The World Health Organization estimates that dementia affects more than 35 million people worldwide, a number expected to more than double by 2030. Problems in the brain related to dementia, such as reduced blood flow, might be present for years but are not evident because of cognitive reserve, a phenomenon where other parts of the brain compensate for deficits in one area. Early detection of cognitive decline is critical, because treatments for Alzheimer’s disease, the most common type of dementia, are most effective in this early phase.
Researchers recently studied arterial spin labeling (ASL), a promising MRI technique that doesn’t require injection of a contrast agent. ASL measures brain perfusion, or penetration of blood into the tissue.
"ASL MRI is simple to perform, doesn’t require special equipment and only adds a few minutes to the exam," said study author Sven Haller, M.D., from the University of Geneva in Geneva, Switzerland.
The study group included 148 healthy elderly participants and 65 people with mild cognitive impairment (MCI). The participants underwent brain MRI and a neuropsychological assessment, a common battery of tests used to determine cognitive ability.
Of the 148 healthy individuals, 75 remained stable, while 73 deteriorated cognitively at 18 months clinical follow-up. Those who deteriorated had shown reduced perfusion at their baseline ASL MRI exams, particularly in the posterior cingulate cortex, an area in the middle of the brain that is associated with the default mode network, the neural network that is active when the brain is not concentrating on a specific task. Declines in this network are seen in MCI patients and are more pronounced in those with Alzheimer’s disease.
The pattern of reduced perfusion in the brains of healthy individuals who went on to develop cognitive deficits was similar to that of patients with MCI.
"There is a known close link between neural activity and brain perfusion in the posterior cingulate cortex," Dr. Haller said. "Less perfusion indicates decreased neural activity."
The results suggest that individuals with decreased perfusion detected with ASL MRI may temporarily maintain their cognitive status through the mobilization of their cognitive reserve, but will eventually develop subtle cognitive deficits.
Previous research done with positron emission tomography (PET), the current gold standard for brain metabolism imaging, found that patients with Alzheimer’s disease had reduced metabolism in the same area of the brain where the perfusion abnormalities were found using ASL MRI. This points to a close link between brain metabolism and perfusion, according to Dr. Haller.
ASL MRI has potential as a standalone test or as an adjunct to PET for dementia screening, Dr. Haller said. While PET can identify markers of Alzheimer’s disease in the brain and cerebrospinal fluid, it exposes the patient to radiation. ASL does not expose the patient to radiation and is easy to perform in routine clinical settings.
"ASL might replace the classic yet unspecific fluordesoxyglucose PET that measures brain metabolism. Instead, PET could be done with the new and specific amyloid PET tracers," Dr. Haller said.
The results also support a role for ASL MRI as an alternative to neuropsychological testing.
The researchers plan to perform follow-up studies on the patient group to learn more about ASL and long-term cognitive changes.

MRI Technique Detects Evidence of Cognitive Decline Before Symptoms Appear

A magnetic resonance imaging (MRI) technique can detect signs of cognitive decline in the brain even before symptoms appear, according to a new study published online in the journal Radiology. The technique has the potential to serve as a biomarker in very early diagnosis of preclinical dementia.

The World Health Organization estimates that dementia affects more than 35 million people worldwide, a number expected to more than double by 2030. Problems in the brain related to dementia, such as reduced blood flow, might be present for years but are not evident because of cognitive reserve, a phenomenon where other parts of the brain compensate for deficits in one area. Early detection of cognitive decline is critical, because treatments for Alzheimer’s disease, the most common type of dementia, are most effective in this early phase.

Researchers recently studied arterial spin labeling (ASL), a promising MRI technique that doesn’t require injection of a contrast agent. ASL measures brain perfusion, or penetration of blood into the tissue.

"ASL MRI is simple to perform, doesn’t require special equipment and only adds a few minutes to the exam," said study author Sven Haller, M.D., from the University of Geneva in Geneva, Switzerland.

The study group included 148 healthy elderly participants and 65 people with mild cognitive impairment (MCI). The participants underwent brain MRI and a neuropsychological assessment, a common battery of tests used to determine cognitive ability.

Of the 148 healthy individuals, 75 remained stable, while 73 deteriorated cognitively at 18 months clinical follow-up. Those who deteriorated had shown reduced perfusion at their baseline ASL MRI exams, particularly in the posterior cingulate cortex, an area in the middle of the brain that is associated with the default mode network, the neural network that is active when the brain is not concentrating on a specific task. Declines in this network are seen in MCI patients and are more pronounced in those with Alzheimer’s disease.

The pattern of reduced perfusion in the brains of healthy individuals who went on to develop cognitive deficits was similar to that of patients with MCI.

"There is a known close link between neural activity and brain perfusion in the posterior cingulate cortex," Dr. Haller said. "Less perfusion indicates decreased neural activity."

The results suggest that individuals with decreased perfusion detected with ASL MRI may temporarily maintain their cognitive status through the mobilization of their cognitive reserve, but will eventually develop subtle cognitive deficits.

Previous research done with positron emission tomography (PET), the current gold standard for brain metabolism imaging, found that patients with Alzheimer’s disease had reduced metabolism in the same area of the brain where the perfusion abnormalities were found using ASL MRI. This points to a close link between brain metabolism and perfusion, according to Dr. Haller.

ASL MRI has potential as a standalone test or as an adjunct to PET for dementia screening, Dr. Haller said. While PET can identify markers of Alzheimer’s disease in the brain and cerebrospinal fluid, it exposes the patient to radiation. ASL does not expose the patient to radiation and is easy to perform in routine clinical settings.

"ASL might replace the classic yet unspecific fluordesoxyglucose PET that measures brain metabolism. Instead, PET could be done with the new and specific amyloid PET tracers," Dr. Haller said.

The results also support a role for ASL MRI as an alternative to neuropsychological testing.

The researchers plan to perform follow-up studies on the patient group to learn more about ASL and long-term cognitive changes.

Filed under dementia cognitive decline arterial spin labeling MRI neuroimaging neuroscience science

219 notes

Vitamin D in diet might ease effects of age on memory
If you don’t want to dumb down with age, vitamin D may be the meal ticket.
A boosted daily dosage of the vitamin over several months helped middle-aged rats navigate a difficult water maze better than their lower-dosed cohorts, according to a study published online Monday in the journal Proceedings of the National Academy of Sciences.
The supplement appears to boost the machinery that helps recycle and repackage signaling chemicals that help neurons communicate with one another in a part of the brain that is central to memory and learning.
"This process is like restocking shelves in grocery stores," said study co-author Nada Porter, a biomedical pharmacologist at the University of Kentucky College of Medicine.
Read more

Vitamin D in diet might ease effects of age on memory

If you don’t want to dumb down with age, vitamin D may be the meal ticket.

A boosted daily dosage of the vitamin over several months helped middle-aged rats navigate a difficult water maze better than their lower-dosed cohorts, according to a study published online Monday in the journal Proceedings of the National Academy of Sciences.

The supplement appears to boost the machinery that helps recycle and repackage signaling chemicals that help neurons communicate with one another in a part of the brain that is central to memory and learning.

"This process is like restocking shelves in grocery stores," said study co-author Nada Porter, a biomedical pharmacologist at the University of Kentucky College of Medicine.

Read more

Filed under vitamin d memory learning cognitive decline cognitive function neuroscience science

516 notes

Memory loss associated with Alzheimer’s reversed for first time
Since its first description over 100 years ago, Alzheimer’s disease has been without effective treatment. That may finally be about to change: in the first, small study of a novel, personalized and comprehensive program to reverse memory loss, nine of 10 participants, including the ones above, displayed subjective or objective improvement in their memories beginning within 3-to-6 months after the program’s start. Of the six patients who had to discontinue working or were struggling with their jobs at the time they joined the study, all were able to return to work or continue working with improved performance. Improvements have been sustained, and as of this writing the longest patient follow-up is two and one-half years from initial treatment. These first ten included patients with memory loss associated with Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI; when a patient reports cognitive problems). One patient, diagnosed with late stage Alzheimer’s, did not improve.
The study, which comes jointly from the UCLA Mary S. Easton Center for Alzheimer’s Disease Research and the Buck Institute for Research on Aging, is the first to suggest that memory loss in patients may be reversed, and improvement sustained, using a complex, 36-point therapeutic program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.
The findings, published in the current online edition of the journal Aging, “are very encouraging. However, at the current time the results are anecdotal, and therefore a more extensive, controlled clinical trial is warranted,” said Dale Bredesen, the Augustus Rose Professor of Neurology and Director of the Easton Center at UCLA, a professor at the Buck Institute, and the author of the paper.
In the case of Alzheimer’s disease, Bredesen notes, there is not one drug that has been developed that stops or even slows the disease’s progression, and drugs have only had modest effects on symptoms. “In the past decade alone, hundreds of clinical trials have been conducted for Alzheimer’s at an aggregate cost of over a billion dollars, without success,” he said.
Other chronic illnesses such as cardiovascular disease, cancer, and HIV, have been improved through the use of combination therapies, he noted. Yet in the case of Alzheimer’s and other memory disorders, comprehensive combination therapies have not been explored. Yet over the past few decades, genetic and biochemical research has revealed an extensive network of molecular interactions involved in AD pathogenesis. “That suggested that a broader-based therapeutics approach, rather than a single drug that aims at a single target, may be feasible and potentially more effective for the treatment of cognitive decline due to Alzheimer’s,” said Bredesen.
While extensive preclinical studies from numerous laboratories have identified single pathogenetic targets for potential intervention, in human studies, such single target therapeutic approaches have not borne out. But, said Bredesen, it’s possible addressing multiple targets within the network underlying AD may be successful even when each target is affected in a relatively modest way. “In other words,” he said, “the effects of the various targets may be additive, or even synergistic.”
The uniform failure of drug trials in Alzheimer’s influenced Bredesen’s research to get a better understanding of the fundamental nature of the disease. His laboratory has found evidence that Alzheimer’s disease stems from an imbalance in nerve cell signaling: in the normal brain, specific signals foster nerve connections and memory making, while balancing signals support memory loss, allowing irrelevant information to be forgotten. But in Alzheimer’s disease, the balance of these opposing signals is disturbed, nerve connections are suppressed, and memories are lost.
The model of multiple targets and an imbalance in signaling runs contrary to the popular dogma that Alzheimer’s is a disease of toxicity, caused by the accumulation of sticky plaques in the brain. Bredesen believes the amyloid beta peptide, the source of the plaques, has a normal function in the brain – as part of a larger set of molecules that promotes signals that cause nerve connections to lapse. Thus the increase in the peptide that occurs in Alzheimer’s disease shifts the memory-making vs. memory-breaking balance in favor of memory loss.
Given all this, Bredesen thought that rather than a single targeted agent, the solution might be a systems type approach, the kind that is in line with the approach taken with other chronic illnesses—a multiple-component system.
“The existing Alzheimer’s drugs affect a single target, but Alzheimer’s disease is more complex. Imagine having a roof with 36 holes in it, and your drug patched one hole very well—the drug may have worked, a single “hole” may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much.”
Bredesen’s approach is personalized to the patient, based on extensive testing to determine what is affecting the plasticity signaling network of the brain. As one example, in the case of the patient with the demanding job who was forgetting her way home, her therapeutic program consisted of some, but not all of the components involved with Bredesen’s therapeutic program, and included:
(1) eliminating all simple carbohydrates, leading to a weight loss of 20 pounds; (2) eliminating gluten and processed food from her diet, with increased vegetables, fruits, and non-farmed fish; (3) to reduce stress, she began yoga; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; (5) she took melatonin each night; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin each day; (8) she took vitamin D3 each day; (9) fish oil each day; (10) CoQ10 each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated hormone replacement therapy that had been discontinued; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week.
The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. “This is the first successful demonstration,” he noted, but he cautioned that the results are anecdotal, and therefore a more extensive, controlled clinical trial is needed.
The downside to this program is its complexity. It is not easy to follow, with the burden falling on the patients and caregivers, and none of the patients were able to stick to the entire protocol. The significant diet and lifestyle changes, and multiple pills required each day, were the two most common complaints. The good news, though, said Bredesen, are the side effects: “It is noteworthy that the major side effect of this therapeutic system is improved health and an optimal body mass index, a stark contrast to the side effects of many drugs.”
The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. “This is the first successful demonstration,” he noted, but he cautioned that the results need to be replicated. “The current, anecdotal results require a larger trial, not only to confirm or refute the results reported here, but also to address key questions raised, such as the degree of improvement that can be achieved routinely, how late in the course of cognitive decline reversal can be effected, whether such an approach may be effective in patients with familial Alzheimer’s disease, and last, how long improvement can be sustained,” he said.
Cognitive decline is a major concern of the aging population. Already, Alzheimer’s disease affects approximately 5.4 million Americans and 30 million people globally. Without effective prevention and treatment, the prospects for the future are bleak. By 2050, it’s estimated that 160 million people globally will have the disease, including 13 million Americans, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer’s disease is on the rise—recent estimates suggest that AD has become the third leading cause of death in the United States behind cardiovascular disease and cancer.
(Image: Corbis)

Memory loss associated with Alzheimer’s reversed for first time

Since its first description over 100 years ago, Alzheimer’s disease has been without effective treatment. That may finally be about to change: in the first, small study of a novel, personalized and comprehensive program to reverse memory loss, nine of 10 participants, including the ones above, displayed subjective or objective improvement in their memories beginning within 3-to-6 months after the program’s start. Of the six patients who had to discontinue working or were struggling with their jobs at the time they joined the study, all were able to return to work or continue working with improved performance. Improvements have been sustained, and as of this writing the longest patient follow-up is two and one-half years from initial treatment. These first ten included patients with memory loss associated with Alzheimer’s disease (AD), amnestic mild cognitive impairment (aMCI), or subjective cognitive impairment (SCI; when a patient reports cognitive problems). One patient, diagnosed with late stage Alzheimer’s, did not improve.

The study, which comes jointly from the UCLA Mary S. Easton Center for Alzheimer’s Disease Research and the Buck Institute for Research on Aging, is the first to suggest that memory loss in patients may be reversed, and improvement sustained, using a complex, 36-point therapeutic program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.

The findings, published in the current online edition of the journal Aging, “are very encouraging. However, at the current time the results are anecdotal, and therefore a more extensive, controlled clinical trial is warranted,” said Dale Bredesen, the Augustus Rose Professor of Neurology and Director of the Easton Center at UCLA, a professor at the Buck Institute, and the author of the paper.

In the case of Alzheimer’s disease, Bredesen notes, there is not one drug that has been developed that stops or even slows the disease’s progression, and drugs have only had modest effects on symptoms. “In the past decade alone, hundreds of clinical trials have been conducted for Alzheimer’s at an aggregate cost of over a billion dollars, without success,” he said.

Other chronic illnesses such as cardiovascular disease, cancer, and HIV, have been improved through the use of combination therapies, he noted. Yet in the case of Alzheimer’s and other memory disorders, comprehensive combination therapies have not been explored. Yet over the past few decades, genetic and biochemical research has revealed an extensive network of molecular interactions involved in AD pathogenesis. “That suggested that a broader-based therapeutics approach, rather than a single drug that aims at a single target, may be feasible and potentially more effective for the treatment of cognitive decline due to Alzheimer’s,” said Bredesen.

While extensive preclinical studies from numerous laboratories have identified single pathogenetic targets for potential intervention, in human studies, such single target therapeutic approaches have not borne out. But, said Bredesen, it’s possible addressing multiple targets within the network underlying AD may be successful even when each target is affected in a relatively modest way. “In other words,” he said, “the effects of the various targets may be additive, or even synergistic.”

The uniform failure of drug trials in Alzheimer’s influenced Bredesen’s research to get a better understanding of the fundamental nature of the disease. His laboratory has found evidence that Alzheimer’s disease stems from an imbalance in nerve cell signaling: in the normal brain, specific signals foster nerve connections and memory making, while balancing signals support memory loss, allowing irrelevant information to be forgotten. But in Alzheimer’s disease, the balance of these opposing signals is disturbed, nerve connections are suppressed, and memories are lost.

The model of multiple targets and an imbalance in signaling runs contrary to the popular dogma that Alzheimer’s is a disease of toxicity, caused by the accumulation of sticky plaques in the brain. Bredesen believes the amyloid beta peptide, the source of the plaques, has a normal function in the brain – as part of a larger set of molecules that promotes signals that cause nerve connections to lapse. Thus the increase in the peptide that occurs in Alzheimer’s disease shifts the memory-making vs. memory-breaking balance in favor of memory loss.

Given all this, Bredesen thought that rather than a single targeted agent, the solution might be a systems type approach, the kind that is in line with the approach taken with other chronic illnesses—a multiple-component system.

“The existing Alzheimer’s drugs affect a single target, but Alzheimer’s disease is more complex. Imagine having a roof with 36 holes in it, and your drug patched one hole very well—the drug may have worked, a single “hole” may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much.”

Bredesen’s approach is personalized to the patient, based on extensive testing to determine what is affecting the plasticity signaling network of the brain. As one example, in the case of the patient with the demanding job who was forgetting her way home, her therapeutic program consisted of some, but not all of the components involved with Bredesen’s therapeutic program, and included:

(1) eliminating all simple carbohydrates, leading to a weight loss of 20 pounds; (2) eliminating gluten and processed food from her diet, with increased vegetables, fruits, and non-farmed fish; (3) to reduce stress, she began yoga; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; (5) she took melatonin each night; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin each day; (8) she took vitamin D3 each day; (9) fish oil each day; (10) CoQ10 each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated hormone replacement therapy that had been discontinued; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week.

The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. “This is the first successful demonstration,” he noted, but he cautioned that the results are anecdotal, and therefore a more extensive, controlled clinical trial is needed.

The downside to this program is its complexity. It is not easy to follow, with the burden falling on the patients and caregivers, and none of the patients were able to stick to the entire protocol. The significant diet and lifestyle changes, and multiple pills required each day, were the two most common complaints. The good news, though, said Bredesen, are the side effects: “It is noteworthy that the major side effect of this therapeutic system is improved health and an optimal body mass index, a stark contrast to the side effects of many drugs.”

The results for nine of the 10 patients reported in the paper suggest that memory loss may be reversed, and improvement sustained with this therapeutic program, said Bredesen. “This is the first successful demonstration,” he noted, but he cautioned that the results need to be replicated. “The current, anecdotal results require a larger trial, not only to confirm or refute the results reported here, but also to address key questions raised, such as the degree of improvement that can be achieved routinely, how late in the course of cognitive decline reversal can be effected, whether such an approach may be effective in patients with familial Alzheimer’s disease, and last, how long improvement can be sustained,” he said.

Cognitive decline is a major concern of the aging population. Already, Alzheimer’s disease affects approximately 5.4 million Americans and 30 million people globally. Without effective prevention and treatment, the prospects for the future are bleak. By 2050, it’s estimated that 160 million people globally will have the disease, including 13 million Americans, leading to potential bankruptcy of the Medicare system. Unlike several other chronic illnesses, Alzheimer’s disease is on the rise—recent estimates suggest that AD has become the third leading cause of death in the United States behind cardiovascular disease and cancer.

(Image: Corbis)

Filed under alzheimer's disease memory loss aging cognitive decline neuroscience science

145 notes

Scientists Identify the Signature of Aging in the Brain

How the brain ages is still largely an open question – in part because this organ is mostly insulated from direct contact with other systems in the body, including the blood and immune systems. In research that was recently published in Science, Weizmann Institute researchers Prof. Michal Schwartz of the Neurobiology Department and Dr. Ido Amit of Immunology Department found evidence of a unique “signature” that may be the “missing link” between cognitive decline and aging. The scientists believe that this discovery may lead, in the future, to treatments that can slow or reverse cognitive decline in older people.

image

(Image caption: Immunofluorescence microscope image of the choroid plexus. Epithelial cells are in green and chemokine proteins (CXCL10) are in red)

Until a decade ago, scientific dogma held that the blood-brain barrier prevents the blood-borne immune cells from attacking and destroying brain tissue. Yet in a long series of studies, Schwartz’s group had shown that the immune system actually plays an important role both in healing the brain after injury and in maintaining the brain’s normal functioning. They have found that this brain-immune interaction occurs across a barrier that is actually a unique interface within the brain’s territory.

This interface, known as the choroid plexus, is found in each of the brain’s four ventricles, and it separates the blood from the cerebrospinal fluid. Schwartz: “The choroid plexus acts as a ‘remote control’ for the immune system to affect brain activity. Biochemical ‘danger’ signals released from the brain are sensed through this interface; in turn, blood-borne immune cells assist by communicating with the choroid plexus. This cross-talk is important for preserving cognitive abilities and promoting the generation of new brain cells.”

This finding led Schwartz and her group to suggest that cognitive decline over the years may be connected not only to one’s “chronological age” but also to one’s “immunological age,” that is, changes in immune function over time might contribute to changes in brain function – not necessarily in step with the count of one’s years.

To test this theory, Schwartz and research students Kuti Baruch and Aleksandra Deczkowska teamed up with Amit and his research group in the Immunology Department. The researchers used next-generation sequencing technology to map changes in gene expression in 11 different organs, including the choroid plexus, in both young and aged mice, to identify and compare pathways involved in the aging process.

That is how they identified a strikingly unique “signature of aging” that exists solely in the choroid plexus – not in the other organs. They discovered that one of the main elements of this signature was interferon beta – a protein that the body normally produces to fight viral infection. This protein appears to have a negative effect on the brain: When the researchers injected an antibody that blocks interferon beta activity into the cerebrospinal fluid of the older mice, their cognitive abilities were restored, as was their ability to form new brain cells. The scientists were also able to identify this unique signature in elderly human brains. The scientists hope that this finding may, in the future, help prevent or reverse cognitive decline in old age, by finding ways to rejuvenate the “immunological age” of the brain.

(Source: wis-wander.weizmann.ac.il)

Filed under aging cognitive decline brain function blood-brain barrier choroid plexus gene expression neuroscience science

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MS researchers find role for working memory in cognitive reserve

Kessler Foundation scientists have shown that working memory may  be an underlying mechanism of cognitive reserve in multiple sclerosis (MS). This finding informs the relationships between working memory, intellectual enrichment (the proxy measure for cognitive reserve) and long-term memory in this population. “Working memory mediates the relationship between intellectual enrichment and long-term memory in multiple sclerosis: An exploratory analysis of cognitive reserve” was published online ahead of print by the Journal of the International Neuropsychological Society on July 14. The authors are Joshua Sandry, PhD, and research scientist James F. Sumowski, PhD, of Neuropsychological & Neuroscience Research at Kessler Foundation. Dr. Sandry is a postdoctoral fellow funded by a grant from the National MS Society.

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Cognitive symptoms, including deficits in long-term memory, are known to affect approximately half of individuals with MS. This study was conducted in 70 patients with MS, who were evaluated for intellectual enrichment, verbal long-term memory, and working memory capacity. “We found that working memory capacity explained the relationship between intellectual enrichment and long-term memory in this population,” said Dr Sandry. “This suggests that interventions targeted at working memory in people with MS may help build cognitive reserve to protect against decline in long-term memory.”

(Source: kesslerfoundation.org)

Filed under MS working memory LTM cognitive reserve cognitive decline neuroscience science

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The effects of very early Alzheimer’s disease on the characteristics of writing by a renowned author

Iris Murdoch (I.M.) was among the most celebrated British writers of the post-war era. Her final novel, however, received a less than enthusiastic critical response on its publication in 1995. Not long afterwards, I.M. began to show signs of insidious cognitive decline, and received a diagnosis of Alzheimer’s disease, which was confirmed histologically after her death in 1999. Anecdotal evidence, as well as the natural history of the condition, would suggest that the changes of Alzheimer’s disease were already established in I.M. while she was writing her final work. The end product was unlikely, however, to have been influenced by the compensatory use of dictionaries or thesauri, let alone by later editorial interference. These facts present a unique opportunity to examine the effects of the early stages of Alzheimer’s disease on spontaneous written output from an individual with exceptional expertise in this area. Techniques of automated textual analysis were used to obtain detailed comparisons among three of her novels: her first published work, a work written during the prime of her creative life and the final novel. Whilst there were few disparities at the levels of overall structure and syntax, measures of lexical diversity and the lexical characteristics of these three texts varied markedly and in a consistent fashion. This unique set of findings is discussed in the context of the debate as to whether syntax and semantics decline separately or in parallel in patients with Alzheimer’s disease.

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Filed under Iris Murdoch alzheimer's disease cognitive decline hippocampus semantics syntax neuroscience science

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Targeted brain training may help you multitask better

The area of the brain involved in multitasking and ways to train it have been identified by a research team at the IUGM Institut universitaire de gériatrie de Montréal and the University of Montreal. The research includes a model to better predict the effectiveness of this training. Cooking while having a conversation, watching a movie while browsing the Web, or driving while listening to a radio show – multitasking is an essential skill in our daily lives. Unfortunately, it decreases with age, which makes it harder for seniors to keep up, causes them stress, and decreases their confidence. Many commercial software applications promise to improve this ability through exercises. But are these exercises truly effective, and how do they work on the brain? The team addresses these issues in two papers published in AGE and PLOS ONE.

Targeted Action for a Specific Result

The findings are important because they may help scientists develop better targeted cognitive stimulation programs or improve existing training programs. Specialists sometimes question the usefulness of exercises that may be ineffective simply because they are poorly structured. “To improve your cardiovascular fitness, most people know you need to run laps on the track and not work on your flexibility. But the way targeted training correlates to cognition has been a mystery for a long time. Our work shows that there is also an association between the type of cognitive training performed and the resulting effect. This is true for healthy seniors who want to improve their attention or memory and is particularly important for patients who suffer from damage in specific areas of the brain. We therefore need to better understand the ways to activate certain areas of the brain and target this action to get specific results,” explained Sylvie Belleville, who led the research.

Researchers are now better able to map these effects on the functioning of very specific areas of the brain. Will we eventually be able to adapt the structure of our brains through highly targeted training? “We have a long road ahead to get to that point, and we don’t know for sure if that would indeed be a desirable outcome. However, our research findings can be used right away to improve the daily lives of aging adults as well as people who suffer from brain damage,” Dr. Belleville said.

The Right Combination of Plasticity and Attentional Control

In one of the studies, 48 seniors were randomly allocated to training that either worked on plasticity and attentional control or only involved simple practice. The researchers used functional magnetic resonance imaging to evaluate the impact of this training on various types of attentional tasks and on brain function. The team showed that training on plasticity and attentional control helped the participants develop their ability to multitask. However, performing two tasks simultaneously was not what improved this skill. For the exercises, the research participants instead had to modulate the amount of attention given to each task. They were first asked to devote 80% of their attention to task A and 20% to task B and then change the ratio to 50:50 or 20:80. This training was the only type that increased functioning in the middle prefrontal region, or the area known to be responsible for multitasking abilities and whose activation decreases with age. The researchers used this data to create a predictive model of the effects of cognitive training on the brain based on the subjects’ characteristics.

(Source: eurekalert.org)

Filed under multitasking aging cognitive decline cognitive training plasticity neuroscience science

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Slow Walking Speed and Memory Complaints Can Predict Dementia

A study involving nearly 27,000 older adults on five continents found that nearly 1 in 10 met criteria for pre-dementia based on a simple test that measures how fast people walk and whether they have cognitive complaints. People who tested positive for pre-dementia were twice as likely as others to develop dementia within 12 years. The study, led by scientists at Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, was published online on July 16, 2014 in Neurology®, the medical journal of the American Academy of Neurology.

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The new test diagnoses motoric cognitive risk syndrome (MCR). Testing for the newly described syndrome relies on measuring gait speed (our manner of walking) and asking a few simple questions about a patient’s cognitive abilities, both of which take just seconds. The test is not reliant on the latest medical technology and can be done in a clinical setting, diagnosing people in the early stages of the dementia process. Early diagnosis is critical because it allows time to identify and possibly treat the underlying causes of the disease, which may delay or even prevent the onset of dementia in some cases.

“In many clinical and community settings, people don’t have access to the sophisticated tests—biomarker assays, cognitive tests or neuroimaging studies—used to diagnose people at risk for developing dementia,” said Joe Verghese, M.B.B.S., professor in the Saul R. Korey Department of Neurology and of medicine at Einstein, chief of geriatrics at Einstein and Montefiore, and senior author of the Neurology paper. “Our assessment method could enable many more people to learn if they’re at risk for dementia, since it avoids the need for complex testing and doesn’t require that the test be administered by a neurologist. The potential payoff could be tremendous—not only for individuals and their families, but also in terms of healthcare savings for society. All that’s needed to assess MCR is a stopwatch and a few questions, so primary care physicians could easily incorporate it into examinations of their older patients.”

The U.S. Centers for Disease Control and Prevention estimates that up to 5.3 million Americans—about 1 in 9 people age 65 and over—have Alzheimer’s disease, the most common type of dementia. That number is expected to more than double by 2050 due to population aging.

“As a young researcher, I examined hundreds of patients and noticed that if an older person was walking slowly, there was a good chance that his cognitive tests were also abnormal,” said Dr. Verghese, who is also the Murray D. Gross Memorial Faculty Scholar in Gerontology at Einstein. “This gave me the idea that perhaps we could use this simple clinical sign—how fast someone walks—to predict who would develop dementia. In a 2002 New England Journal of Medicine study, we reported that abnormal gait patterns accurately predict whether people will go on to develop dementia. MCR improves on the slow gait concept by evaluating not only patients’ gait speed but also whether they have cognitive complaints.”

The Neurology paper reported on the prevalence of MCR among 26,802 adults without dementia or disability aged 60 years and older enrolled in 22 studies in 17 countries. A significant number of adults—9.7 percent—met the criteria for MCR (i.e., abnormally slow gait and cognitive complaints). While the syndrome was equally common in men and women, highly educated people were less likely to test positive for MCR compared with less-educated individuals. A slow gait, said Dr. Verghese, is a walking speed slower than about one meter per second, which is about 2.2 miles per hour (m.p.h.). Less than 0.6 meters per second (or 1.3 m.p.h.) is “clearly abnormal.”

To test whether MCR predicts future dementia, the researchers focused on four of the 22 studies that tested a total of 4,812 people for MCR and then evaluated them annually over an average follow-up period of 12 years to see which ones developed dementia. Those who met the criteria for MCR were nearly twice as likely to develop dementia over the following 12 years compared with people who did not.

Dr. Verghese emphasized that a slow gait alone is not sufficient for a diagnosis of MCR. “Walking slowly could be due to conditions such as arthritis or an inner ear problem that affects balance, which would not increase risk for dementia. To meet the criteria for MCR requires having a slow gait and cognitive problems. An example would be answering ‘yes’ to the question, ‘Do you think you have more memory problems than other people?’”

For patients meeting MCR criteria, said Dr. Verghese, the next step is to look for the causes of their slow gait and cognitive complaints. The search may reveal underlying—and controllable—problems. “Evidence increasingly suggests that brain health is closely tied to cardiovascular health—meaning that treatable conditions such as hypertension, smoking, high cholesterol, obesity and diabetes can interfere with blood flow to the brain and thereby increase a person’s risk for developing Alzheimer’s and other dementias,” said Dr. Verghese.

What about people who meet MCR criteria but no treatable underlying problems can be found?

“Even in the absence of a specific cause, we know that most healthy lifestyle factors, such as exercising and eating healthier, have been shown to reduce the rate of cognitive decline,” said Dr. Verghese. “In addition, our group has shown that cognitively stimulating activities—playing board games, card games, reading, writing and also dancing—can delay dementia’s onset. Knowing they’re at high risk for dementia can also help people and their families make arrangements for the future, which is an aspect of MCR testing that I’ve found is very important in my own clinical practice.”

Filed under dementia motoric cognitive risk syndrome gait speed cognitive decline neuroscience science

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