Posts tagged cognitive impairment
Articles and news from the latest research reports.
Fetal exposure to antiepileptic drug valproate impairs cognitive development
The effects of antiepileptic drugs during pregnancy have long been a concern of clinicians and women of childbearing age whose seizures can only be controlled by medications. In 1999, a study called the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) began following the children of women who were taking a single antiepileptic agent during pregnancy. The drugs included carbamazepine, lamotrigine, phenytoin or valproate.
Recently released final data from NEAD shows that at age 6, IQ is 7-10 points lower in children exposed in utero to the anti-epileptic drug valproate (Depakote) than those exposed to the other medications. The children exposed to valproate also did poorly on measures of verbal and memory abilities, and non-verbal and executive functions. The results were reported in the January 23, 2013, Lancet Neurology publication on line.
"Data published at ages 3 and 4.5 showed similar results in cognitive impairment," says lead study author Kimford Meador, MD, professor of neurology at Emory University School of Medicine. "Age 6 IQ was our primary outcome goal because it is standardized and predictive of school performance."
The NEAD study is the largest prospective study examining the cognitive effects of fetal antiepileptic drug exposure. The researchers monitored women through pregnancy and followed their children, performing cognitive testing at ages 2,3,4.5 and finally at 6. In addition to the effect on cognitive function, earlier data from NEAD showed an increase in the risk of anatomical birth defects.
Valproate is an anticonvulsant used in the treatment of epilepsy, migraines and bipolar disorder, and is particularly effective in the treatment of primary generalized seizures. Except for a small number of women who only respond to valproate, there are alternative medications.
"These findings consistently show a substantial loss of developmental abilities for these children," says Meador. "Women of childbearing age who have epilepsy should talk with their doctors about their options, and possibly test the safer medications prior to pregnancy to find out if they work."
In order to avoid seizures with potentially serious consequences, Meador emphasizes that women who are already pregnant and taking valproate should not stop without consulting their physicians.
"For a woman who has significant seizures, the risk from the seizure itself is worse than the risk of taking the drugs," he points out. "The number one reason for miscarriage late in pregnancy for women with epilepsy is trauma resulting from a seizure."
Meador will co-lead a follow-up study with Page Pennell, MD, from Harvard. The new study funded by the National Institutes of Health is called Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD), and will investigate the risks of these same drugs to both the mother and the child. The study will be conducted at 19 sites, enrolling 350 women with epilepsy during pregnancy. An additional 100 women with epilepsy who are not pregnant, and 100 healthy pregnant women will serve as controls.
(Source: news.emory.edu)
Improved Detection of Frontotemporal Degeneration May Aid Clinical Trial Efforts
A series of studies demonstrate improved detection of the second most common form of dementia, providing diagnostic specificity that clears the way for refined clinical trials testing targeted treatments. The new research is being presented by experts from the Perelman School of Medicine at the University of Pennsylvania at the American Academy of Neurology’s 65th Annual Meeting in San Diego March 16-23, 2013.
Frontotemporal degeneration, the most common dementia in people under 60, can be hereditary or sporadic in nature and caused by one of two different mutated proteins (tau or TDP-43). The disease results in damage to the anterior temporal and/or frontal lobes of the brain. As the disease progresses, it becomes increasingly difficult for people to plan or organize activities, behave appropriately in social or work settings, interact with others, and care for oneself, resulting in increasing dependency.
In one study, the team confirmed that a novel multimodal imaging approach was more accurate (88 percent) than using either MRI (72 percent) or DTI (81 percent) alone to detect FTD versus Alzheimer’s disease. The two imaging techniques integrate measures of white matter and grey matter, providing a statistically powerful method for predicting underlying pathology in order to screen patients for clinical trials.
“We are moving forward on our biomarker work to optimize our ability to identify the specific cause of an individual’s difficulties during life, said senior author Murray Grossman, MD, EdD, professor of Neurology and director of the Penn FTLD Center. “We use a novel multi-modality approach involving behavioral, imaging and biofluid biomarker measures.”
In a second study, researchers found that a brief series of neuropsychological tests of memory, word generation and conceptual flexibility (needed for creative problem-solving) helped differentiate people with very mild behavioral variant FTD (bvFTD) and those with mild cognitive impairment (MCI). The combination of tests correctly classified 85.7 percent of bvFTD cases and 83.3 percent of MCI cases at early stages of disease.
“This is particularly important because treatment trials with disease-modifying agents are emerging, often based on animal studies, yet we still don’t have all the tools we need to identify who is most appropriate to participate in one of these trials. Moreover, we can use this information we ascertain to help determine who is responding to a treatment in a clinical trial.”
The third study being presented at the meeting showed that hereditary forms of FTD appear to have more rapid cognitive decline and differing tau profiles compared with sporadic forms of the disease. For clinical trials testing whether a drug can delay damage caused by tau, any known differences in the speed of disease progression could interfere with trial results.
(Image courtesy: University of Pennsylvania)
Study looks to distinguish cognitive functioning in centenarians
As life expectancy continues to increase, more and more people will reach and surpass the century mark in age. But even as greater numbers reach and surpass the 100-year milestone, little is known about what constitutes normal levels of cognitive function in the second century of life.
Led by Adam Davey, associate professor in Temple’s Department of Public Health, a group of researchers used a new method called factor mixture analysis — a statistical technique for identifying different groups within a population — to identify the prevalence of cognitive impairment in centenarians and try to understand the cognitive changes that are part of extreme aging. They published their findings, “Profiles of Cognitive Functioning in a Population-Based Sample of Centenarians Using Factor Mixture Analysis,” in the journal Experimental Aging Research.
“One of the motivations for studying centenarians is that they are very close to the upper limit of human life expectancy right now,” said Davey. “By looking at their cognitive functioning we can learn a lot in terms of how common or prevalent cognitive impairment is among that age group.”
Using voter registration lists and nursing home records in 44 counties in northern Georgia, the researchers identified 244 people between the ages of 98-108 — approximately 20 percent of all centenarians living in that region — who participated in the study. Participants were assessed based on a series of standard tests used to measure cognitive functioning.
“As people get into later life and the prevalence of cognitive impairment becomes relatively high, we need some way of distinguishing between those people who are aging normally and the people who have cognitive impairment, which could indicate dementia,” said Davey.
The researchers found that even though approximately two-thirds of centenarians were at or below the threshold for cognitive impairment by one commonly used measure, only one-third of centenarians were identified as cognitively impaired using their new approach.
“That’s consistent with the level of cognitive impairment found in another study that looked at people up to the age of 85-plus,” said Davey. “But even the normal folks have had cognitive declines to the point that they are functioning at a level that would indicate impairment at younger ages.”
The researchers found that characteristics such as age, race and educational attainment can help to distinguish those in the lower cognitive performance group.
“This is the first study that I’m aware of that allows us to distinguish between these two groups of centenarians, so that we can start to develop benchmarks for what is normal cognitive functioning among members of this age group,” said Davey. “These people have lived so long that even their normal cognitive function could be mistaken for a form of dementia if a physician were to treat them as they would someone who was merely old.”
(Image credit: Krissy_77)
New model could lead to improved treatment for early stage Alzheimer’s
Researchers at the University of Florida and The Johns Hopkins University have developed a line of genetically altered mice that model the earliest stages of Alzheimer’s disease. This model may help scientists identify new therapies to provide relief to patients who are beginning to experience symptoms.
The researchers report their findings in the current issue of The Journal of Neuroscience.
“The development of this model could help scientists identify new ways to enhance brain function in patients in the early stages of the disease,” said David Borchelt, UF professor of neuroscience in the Evelyn F. and William L. McKnight Brain Institute and director of the SantaFe HealthCare Alzheimer’s Disease Research Center. “Such therapies could preserve brain function longer and delay the appearance of more severe symptoms that leave patients unable to care for themselves.”
In the early stages of Alzheimer’s disease, people struggle with and fail to learn new games, rules or technologies because their cognitive flexibility decreases. The degenerative disease continues with memory loss and the decline of other brain functions.
The researchers worked with mice that had specially designed gene fragments derived from bacteria and from humans that allowed the investigators to control the production of a small peptide. The peptide, called amyloid beta peptide, is a short chain of amino acids. Accumulations of this particular peptide in the brain as lesions called plaques occur early in the progression of Alzheimer’s disease and seem to trigger the early memory problems.
The team regulated the expression of the peptide using antibiotics — when the animals stopped taking the antibiotic, the peptide-producing gene turned on and caused the mice to develop the plaques found in Alzheimer’s patients. After the mice had developed the Alzheimer pathology, the researchers turned the gene back off and observed that the mice showed persistent memory problems that resemble the early stages of the disease.
“This model may be useful to researchers to test drugs that could help with symptoms of early stage Alzheimer’s disease,” Borchelt said.This research is funded by the National Institute of Neurological Disease and Stroke of the National Institutes of Health, and the SantaFe HealthCare Alzheimer’s Disease Research Center of the University of Florida.
Gene thought to be linked to Alzheimer’s is marker for only mild impairment
Defying the widely held belief that a specific gene is the biggest risk factor for Alzheimer’s disease, two Cornell developmental psychologists and their colleagues report that people with that gene are more likely to develop mild cognitive impairment — but not Alzheimer’s.
The study suggests that older adults with healthy brain function can get genetic tests to predict increased risk of future mild cognitive impairment. However, once they are impaired cognitively, the tests won’t predict their likelihood of developing Alzheimer’s.
"Right now, genetic tests are used in exactly the opposite way. That is, healthy people don’t get the tests to predict their risk of mild cognitive impairment, but impaired people get them to predict their risk of Alzheimer’s disease," said Charles Brainerd, professor of human development and the study’s lead co-author with Valerie Reyna, professor of human development. "So, impaired people think that tests will tell them if they are at increased risk of Alzheimer’s, which they won’t. And healthy people think that tests won’t tell them whether they are at increased risk of cognitive impairment, which they will."
The researchers describe their findings in the January issue of Neuropsychology (27:1).
The work builds on previous research by Brainerd and associates that suggested the ε4 allele of the APOE genotype increases the risk of mild cognitive impairment as well as Alzheimer’s.
The researchers analyzed data from the only nationally representative dataset of its kind, the National Institute on Aging’s Aging, Demographics and Memory Study. They looked at data from 418 people over age 70 to see if those who carried the allele were more likely to develop mild cognitive impairment compared with those who did not have the allele. They also looked at whether ε4 carriers with mild cognitive impairment were more likely to develop Alzheimer’s disease compared with non-carriers with mild cognitive impairment.
They found that healthy ε4 carriers were nearly three times — 58 percent — more likely to develop mild cognitive impairment compared with non-carriers. However, ε4 carriers with mild cognitive impairment developed Alzheimer’s at the same rate as non-carriers.
Vascular brain injury greater risk factor than amyloid plaques in cognitive aging
Vascular brain injury from conditions such as high blood pressure and stroke are greater risk factors for cognitive impairment among non-demented older people than is the deposition of the amyloid plaques in the brain that long have been implicated in conditions such as Alzheimer’s disease, a study by researchers at the Alzheimer’s Disease Research Center at UC Davis has found.
Published online early today in JAMA Neurology (formerly Archives of Neurology), the study found that vascular brain injury had by far the greatest influence across a range of cognitive domains, including higher-level thinking and the forgetfulness of mild cognitive decline.
The researchers also sought to determine whether there was a correlation between vascular brain injury and the deposition of beta amyloid (Αβ) plaques, thought to be an early and important marker of Alzheimer’s disease, said Bruce Reed, associate director of the UC Davis Alzheimer’s Disease Research Center in Martinez, Calif. They also sought to decipher what effect each has on memory and executive functioning.
“We looked at two questions,” said Reed, professor in the Department of Neurology at UC Davis. “The first question was whether those two pathologies correlate to each other, and the simple answer is ‘no.’ Earlier research, conducted in animals, has suggested that having a stroke causes more beta amyloid deposition in the brain. If that were the case, people who had more vascular brain injury should have higher levels of beta amyloid. We found no evidence to support that.”
"The second,” Reed continued, “was whether higher levels of cerebrovascular disease or amyloid plaques have a greater impact on cognitive function in older, non-demented adults. Half of the study participants had abnormal levels of beta amyloid and half vascular brain injury, or infarcts. It was really very clear that the amyloid had very little effect, but the vascular brain injury had distinctly negative effects.”
“The more vascular brain injury the participants had, the worse their memory and the worse their executive function – their ability to organize and problem solve,” Reed said.
The research was conducted in 61 male and female study participants who ranged in age from 65 to 90 years old, with an average age of 78. Thirty of the participants were clinically “normal,” 24 were cognitively impaired and seven were diagnosed with dementia, based on cognitive testing. The participants had been recruited from Northern California between 2007 to 2012.
The study participants underwent magnetic resonance imaging (MRI) ― to measure vascular brain injury ― and positron emission tomography (PET) scans to measure beta amyloid deposition: markers of the two most common pathologies that affect the aging brain. Vascular brain injury appears as brain infarcts and “white matter hyperintensities” in MRI scans, areas of the brain that appear bright white.
The study found that both memory and executive function correlated negatively with brain infarcts, especially infarcts in cortical and sub-cortical gray matter. Although infarcts were common in this group, the infarcts varied greatly in size and location, and many had been clinically silent. The level of amyloid in the brain did not correlate with either changes in memory or executive function, and there was no evidence that amyloid interacted with infarcts to impair thinking.
Reed said the study is important because there’s an enormous amount of interest in detecting Alzheimer’s disease at its earliest point, before an individual exhibits clinical symptoms. It’s possible to conduct a brain scan and detect beta amyloid in the brain, and that is a very new development, he said.
“The use of this diagnostic tool will become reasonably widely available within the next couple of years, so doctors will be able to detect whether an older person has abnormal levels of beta amyloid in the brain. So it’s very important to understand the meaning of a finding of beta amyloid deposition,” Reed said.
“What this study says is that doctors should think about this in a little more complicated way. They should not forget about cerebrovascular disease, which is also very common in this age group and could also cause cognitive problems. Even if a person has amyloid plaques, those plaques may not be the cause of their mild cognitive symptoms.”
(Source: ucdmc.ucdavis.edu)
One in Three Children with Multiple Sclerosis has Cognitive Impairment
Data from the largest multicenter study accessing cognitive functioning in children with multiple sclerosis (MS) reveals that one-third of these patients have cognitive impairment, according to a research paper published in the Journal of Child Neurology. Led by Lauren B. Krupp, MD, Director of the Lourie Center for Pediatric Multiple Sclerosis at Stony Brook Long Island Children’s Hospital, the study indicates that patients experience a range of problems related to cognition.
In “Cognitive Impairment Occurs in Children and Adolescents with Multiple Sclerosis: Results from a United States Network,” Dr. Krupp and colleagues from Stony Brook and five other national Pediatric MS Centers of Excellence measured the cognitive functioning of 187 children and adolescents with MS, and 44 who experienced their first neurologic episode (clinically isolated syndrome) indicative of MS. They found that 35 percent of the patients with MS and 18 percent of those with clinically isolated syndrome met criteria for cognitive impairment. All patients were under age 18 with an average disease duration of about two years.
“This study is important because it represents the largest study to date to apply a comprehensive neuropsychological battery of tests to evaluate the cognitive functioning of children with MS, and the results clearly show us that cognitive issues are widespread and can occur early on in the disease course of these patients,” said Dr. Krupp, also a Professor of Neurology at Stony Brook University School of Medicine. “These are critically important findings that emphasize the need for prompt recognition of our patients’ cognitive problems and for neurologists and other MS specialists to discover ways to intervene and help improve the cognitive abilities of these children while they are in school and beyond.”
Cardiac Disease Linked to Higher Risk of Mental Impairment
Cardiac disease is associated with increased risk of mild cognitive impairment such as problems with language, thinking and judgment — particularly among women with heart disease, a Mayo Clinic study shows. Known as nonamnestic because it doesn’t include memory loss, this type of mild cognitive impairment may be a precursor to vascular and other non-Alzheimer’s dementias, according to the findings published online Monday in JAMA Neurology.
Mild cognitive impairment is an important stage for early detection and intervention in dementia, says lead author, Rosebud Roberts, M.B., Ch.B., a health sciences researcher at Mayo Clinic.
"Prevention and management of cardiac disease and vascular risk factors are likely to reduce the risk," Roberts says.
Researchers evaluated 2,719 people ages 70 to 89 at the beginning of the study and every 15 months after. Of the 1,450 without mild cognitive impairment at the beginning, 669 had heart disease and 59 (8.8 percent) developed nonamenestic mild cognitive impairment; in comparison 34 (4.4 percent) of 781 who did not have heart disease developed nonamenestic mild cognitive impairment.
The association varied by sex; cardiac disease and mild cognitive impairment appeared together more often among women than in men.
(Source)
A brain protein called vimentin can indicate damage to the hippocampus following binge drinking
Chronic drinking is known to have detrimental health effects such as cardiac and liver problems, cognitive impairments, and brain damage. Binge drinking in particular is known to increase the risk of developing dementia and/or brain damage, yet little is known about an exact threshold for the damaging effects of alcohol. A study using rodents to examine various markers of neurodegeneration has found that brain damage can occur with as little as 24 hours of binge-like alcohol exposure.
Results will be published in the March 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
"We know that the extent of damage following alcohol exposure depends heavily on the manner in which it is consumed," said Kimberly Nixon, associate professor of pharmaceutical sciences at The University of Kentucky as well as corresponding author for the study. "Human studies suggest that binge-pattern drinking is more closely associated with brain damage. One study, for example, reported that binge drinking at least once per month in adulthood significantly increases the risk of developing dementia later in life. Animal models help provide the critical information that binge drinking, which produces high blood alcohol levels, directly causes damage."
"The exact threshold for the damaging effects of alcohol on the brain is unclear," commented Fulton T. Crews, John Andrews Distinguished Professor and director of the Center for Alcohol Studies at the University of North Carolina. "It is likely that the higher the blood alcohol level the greater the damage, however, this manuscript only studies binge drinking, using vimentin and flurojade B as markers of neurotoxicity."
"People hear from multiple sources that low-moderate alcohol consumption can be beneficial, and then we come along and say that heavy alcohol use leads to detrimental outcomes," said Nixon. "People then want to know what the line is between beneficial and detrimental Unfortunately, we don’t know exactly. However, our study suggests that it may be even less than previously thought."
Nixon and her colleagues administered a nutritionally complete liquid diet to adult male Sprague-Dawley rats that additionally contained either alcohol (25% w/v) or isocaloric dextrose every eight hours for either one or two days. The rodents were sacrificed immediately following, two days after, or seven days after alcohol exposure and their brain tissues were examined.
"This was really a simple study that took advantage of some new ‘tools’ to look for evidence of brain damage," explained Nixon. "In other words, we didn’t look for dying cells themselves, but we looked at more indirect indices of damage by looking at what happens to astroglia, one of the ‘supporting’ cells for neurons. Astroglia react to brain damage by expressing several proteins that they do not normally express under healthy, happy conditions, one of which is an intermediate filament protein called vimentin. We saw a remarkable number of cells expressing this marker It is one of those ‘here is your brain, here is your brain on drugs’ kind of findings where the expression was obvious to the naked eye in many brains with as little as 24 hours of high blood alcohol levels."
Nixon added that, because rodents metabolize alcohol significantly faster than humans do, it is important to look at the actual concentration of alcohol in the blood in order to translate this to the human condition. “These rats had blood alcohol levels that were more than four times the legal driving limit, which for humans would require excessive drinking in the nature of a 12-pack of beer, a couple bottles of wine, or half of fifth of whisky. Unfortunately, drinking self-reports and blood alcohol level data from emergency rooms confirm that this level of drinking is common in those with alcohol use disorders.”
"Rodent brain damage can model human damage," noted Crews. "Vimentin seems to be a good marker of glial activation that shows that one day of binge drinking can cause some brain damage that persists and grows after a week of abstinence. However, both rodent and human brain damage generally require long-term alcohol consumption that models alcoholism and not the acute responses studied in this manuscript."
Nixon agreed. “The lack of overt neuronal deterioration suggests that a single, short-term, high-level binge probably does not result in functional changes and/or cognitive deficits,” she said. “However, since alcoholics experience multiple binges throughout their lifetime, it is important to consider that each successive binge, starting with the very first one, affords some level of damage to the brain. Therefore, theoretically, with multiple binges comes a cumulative detrimental effect where pronounced cognitive, behavioral, and structural effects are observed.”
Nixon said this study demonstrates that new discoveries are always possible. “You have to know where and when to look for some of these effects,” she said. “The reason why this discovery wasn’t made previously is merely due to groups, ourselves included, not taking the time to thoroughly investigate these lower threshold doses with some pretty specific time points. Chasing down a threshold is not a sexy topic and it was actually fairly risky in that it was possible that we would have had all negative effects. Nonetheless, the take-home message of our data is that even one short-duration binge-alcohol experience – which is unfortunately similar to what young adults may experience during spring break or weekend partying - may start a cascade that leads to brain damage.”
(Source: eurekalert.org)
Late-Life Depression Associated with Prevalent Mild Cognitive Impairment, Increased Risk of Dementia
Depression in a group of Medicare recipients ages 65 years and older appears to be associated with prevalent mild cognitive impairment and an increased risk of dementia, according to a report published Online First by Archives of Neurology, a JAMA Network publication.
Depressive symptoms occur in 3 percent to 63 percent of patients with mild cognitive impairment (MCI) and some studies have shown an increased dementia risk in individuals with a history of depression. The mechanisms behind the association between depression and cognitive decline have not been made clear and different mechanisms have been proposed, according to the study background.
Edo Richard, M.D., Ph.D., of the University of Amsterdam, the Netherlands, and colleagues evaluated the association of late-life depression with MCI and dementia in a group of 2,160 community-dwelling Medicare recipients.
“We found that depression was related to a higher risk of prevalent MCI and dementia, incident dementia, and progression from prevalent MCI to dementia, but not to incident MCI,” the authors note.
Baseline depression was associated with prevalent MCI (odds ratio [OR], 1.4) and dementia (OR, 2.2), while baseline depression was associated with an increased risk of incident dementia (hazard ratio [HR], 1.7) but not with incident MCI (HR, 0.9). Patients with MCI and coexisting depression at baseline also had a higher risk of progression to dementia (HR, 2.0), especially vascular dementia (HR, 4.3), but not Alzheimer disease (HR, 1.9), according to the study results.
“Our finding that depression was associated cross sectionally with both MCI and dementia and longitudinally only with dementia suggests that depression develops with the transition from normal cognition to dementia,” the authors conclude.
(Source: media.jamanetwork.com)