Posts tagged cognitive decline
Articles and news from the latest research reports.
Producing new neurones under all circumstances: a challenge that is just a mouse away …
Improving neurone production in elderly persons presenting with a decline in cognition is a major challenge facing an ageing society and the emergence of neuro-degenerative conditions such as Alzheimer’s disease. INSERM and CEA researchers recently showed that the pharmacological blocking of the TGFβ molecule improves the production of new neurones in the mouse model. These results incentivise the development of targeted therapies enabling improved neurone production to alleviate cognitive decline in the elderly and reduce the cerebral lesions caused by radiotherapy.
The research is published in the journal EMBO Molecular Medicine.
New neurones are formed regularly in the adult brain in order to guarantee that all our cognitive capacities are maintained. This neurogenesis may be adversely affected in various situations and especially:
- in the course of ageing,
- after radiotherapy treatment of a brain tumour. (The irradiation of certain areas of the brain is, in fact, a central adjunctive therapy for brain tumours in adults and children).
According to certain studies, the reduction in our “stock” of neurones contributes to an irreversible decline in cognition. In the mouse, for example, researchers reported that exposing the brain to radiation in the order of 15 Gy is accompanied by disruption to the olfactive memory and a reduction in neurogenesis. The same happens in ageing in which a reduction in neurogenesis is associated with a loss of certain cognitive faculties. In patients receiving radiotherapy due to the removal of a brain tumour, the same phenomena can be observed.
Researchers are studying how to preserve the “neurone stock”. To do this, they have tried to discover which factors are responsible for the decline in neurogenesis.
Contrary to what might have been believed, their initial observations show that neither heavy doses of radiation nor ageing are responsible for the complete disappearance of the neural stem cells capable of producing neurones (and thus the origin of neurogenesis). Those that survive remain localised in a certain small area of the brain (the sub-ventricular zone (SVZ)). They nevertheless appear not to be capable of working correctly.
Additional experiments have made it possible to establish that in both situations, irradiation and ageing, high levels of the cytokine TGFβ cause the stem cells to become dormant, increasing their susceptibility to apoptosis (PCD) and reducing the number of new neurones.
“Our study concluded that although neurogenesis reduced in ageing and after a high dose of radiation, many stem cells survive for several months, retaining their ‘stem’ characteristics”, explains Marc-Andre Mouthon, one of the main authors of the research, that was conducted in conjunction with José Piñeda and François Boussin.
The second part of the project demonstrated that pharmacological blocking of TGFβ restores the production of new neurones in irradiated or ageing mice.
For the researchers, these results will encourage the development of targeted therapies to block TGFβ in order to reduce the impact of brain lesions caused by radiotherapy and improving the production of neurones in the elderly presenting with a cognitive decline.
Brain-imaging tool and stroke risk test help identify cognitive decline early
UCLA researchers have used a brain-imaging tool and stroke risk assessment to identify signs of cognitive decline early on in individuals who don’t yet show symptoms of dementia.
The connection between stroke risk and cognitive decline has been well established by previous research. Individuals with higher stroke risk, as measured by factors like high blood pressure, have traditionally performed worse on tests of memory, attention and abstract reasoning.
The current small study demonstrated that not only stroke risk, but also the burden of plaques and tangles, as measured by a UCLA brain scan, may influence cognitive decline.
The imaging tool used in the study was developed at UCLA and reveals early evidence of amyloid beta “plaques” and neurofibrillary tau “tangles” in the brain — the hallmarks of Alzheimer’s disease.
The study, published in the April issue of the Journal of Alzheimer’s Disease, demonstrates that taking both stroke risk and the burden of plaques and tangles into accout may offer a more powerful assessment of factors determining how people are doing now and will do in the future.
"The findings reinforce the importance of managing stroke risk factors to prevent cognitive decline even before clinical symptoms of dementia appear," said first author Dr. David Merrill, an assistant clinical professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA.
This is one of the first studies to examine both stroke risk and plaque and tangle levels in the brain in relation to cognitive decline before dementia has even set in, Merrill said.
According to the researchers, the UCLA brain-imaging tool could prove useful in tracking cognitive decline over time and offer additional insight when used with other assessment tools.
For the study, the team assessed 75 people who were healthy or had mild cognitive impairment, a risk factor for the future development of Alzheimer’s. The average age of the participants was 63.
The individuals underwent neuropsychological testing and physical assessments to calculate their stroke risk using the Framingham Stroke Risk Profile, which examines age, gender, smoking status, systolic blood pressure, diabetes, atrial fibrillation (irregular heart rhythm), use of blood pressure medications, and other factors.
In addition, each participant was injected with a chemical marker called FDDNP, which binds to deposits of amyloid beta plaques and neurofibrillary tau tangles in the brain. The researchers then used positron emission tomography (PET) to image the brains of the subjects — a method that enabled them to pinpoint where these abnormal proteins accumulate.
The study found that greater stroke risk was significantly related to lower performance in several cognitive areas, including language, attention, information-processing speed, memory, visual-spatial functioning (e.g., ability to read a map), problem-solving and verbal reasoning.
The researchers also observed that FDDNP binding levels in the brain correlated with participants’ cognitive performance. For example, volunteers who had greater difficulties with problem-solving and language displayed higher levels of the FDDNP marker in areas of their brain that control those cognitive activities.
"Our findings demonstrate that the effects of elevated vascular risk, along with evidence of plaques and tangles, is apparent early on, even before vascular damage has occurred or a diagnosis of dementia has been confirmed," said the study’s senior author, Dr. Gary Small, director of the UCLA Longevity Center and a professor of psychiatry and biobehavioral sciences who holds the Parlow–Solomon Chair on Aging at UCLA’s Semel Institute.
Researchers found that several individual factors in the stroke assessment stood out as predictors of decline in cognitive function, including age, systolic blood pressure and use of blood pressure–related medications.
Small noted that the next step in the research would be studies with a larger sample size to confirm and expand the findings.
Tests to Predict Heart Problems and Stroke May Be More Useful Predictor of Memory Loss than Dementia Tests
Risk prediction tools that estimate future risk of heart disease and stroke may be more useful predictors of future decline in cognitive abilities, or memory and thinking, than a dementia risk test, according to a new study published in the April 2, 2013, print issue of Neurology®, the medical journal of the American Academy of Neurology.
“This is the first study that compares these risk scores with a dementia risk score to study decline in cognitive abilities 10 years later,” said Sara Kaffashian, PhD, with the French National Institute of Health and Medical Research (INSERM) in Paris, France.
The study involved 7,830 men and women with an average age of 55. Risk of heart disease and stroke (cardiovascular disease) and risk of dementia were calculated for each participant at the beginning of the study. The heart disease risk score included the following risk factors: age, blood pressure, treatment for high blood pressure, high density lipoprotein (HDL) cholesterol, total cholesterol, smoking, and diabetes. The stroke risk score included age, blood pressure, treatment for high blood pressure, diabetes, smoking, history of heart disease, and presence of cardiac arrhythmia (irregular heart beat).
The dementia risk score included age, education, blood pressure, body mass index (BMI), total cholesterol, exercise, and whether a person had the APOE ?4 gene, a gene associated with dementia.
Memory and thinking abilities were measured three times over 10 years.
The study found that all three risk scores predicted 10-year decline in multiple cognitive tests. However, heart disease risk scores showed stronger links with cognitive decline than a dementia risk score. Both heart and stroke risk were associated with decline in all cognitive tests except memory; dementia risk was not linked with decline in memory and verbal fluency.
“Although the dementia and cardiovascular risk scores all predict cognitive decline starting in late middle age, cardiovascular risk scores may have an advantage over the dementia risk score for use in prevention and for targeting changeable risk factors since they are already used by many physicians. The findings also emphasize the importance of risk factors for cardiovascular disease such as high cholesterol and high blood pressure in not only increasing risk of heart disease and stroke but also having a negative impact on cognitive abilities,” said Kaffashian.
Surgical menopause may prime brain for stroke, Alzheimer’s
Women who abruptly and prematurely lose estrogen from surgical menopause have a two-fold increase in cognitive decline and dementia.
"This is what the clinical studies indicate and our animal studies looking at the underlying mechanisms back this up," said Brann, corresponding author of the study in the journal Brain. “We wanted to find out why that is occurring. We suspect it’s due to the premature loss of estrogen.”
In an effort to mimic what occurs in women, Brann and his colleagues looked at rats 10 weeks after removal of their estrogen-producing ovaries that were either immediately started on low-dose estrogen therapy, started therapy 10 weeks later or never given estrogen.
When the researchers caused a stroke-like event in the brain’s hippocampus, a center of learning and memory, they found the rodents treated late or not at all experienced more brain damage, specifically to a region of the hippocampus called CA3 that is normally stroke-resistant.
To make matters worse, untreated or late-treated rats also began an abnormal, robust production of Alzheimer’s disease-related proteins in the CA3 region, even becoming hypersensitive to one of the most toxic of the beta amyloid proteins that are a hallmark of Alzheimer’s.
Both problems appear associated with the increased production of free radicals in the brain. In fact, when the researchers blocked the excessive production, heightened stroke sensitivity and brain cell death in the CA3 region were reduced.
Interestingly the brain’s increased sensitivity to stressors such as inadequate oxygen was gender specific, Brann said. Removing testes in male rats, didn’t affect stroke size or damage.
Although exactly how it works is unknown, estrogen appears to help protect younger females from problems such as stroke and heart attack. Their risks of the maladies increase after menopause to about the same as males. Follow up studies are needed to see if estrogen therapy also reduces sensitivity to the beta amyloid protein in the CA3 region, as they expect, Brann noted.
Brann earlier showed that prolonged estrogen deprivation in aging rats dramatically reduces the number of brain receptors for the hormone as well as its ability to prevent strokes. Damage was forestalled if estrogen replacement was started shortly after hormone levels drop, according to the 2011 study in the journal Proceedings of the National Academy of Sciences.
The surprising results of the much-publicized Women’s Health Initiative – a 12-year study of 161,808 women ages 50-79 – found hormone therapy generally increased rather than decreased stroke risk as well as other health problems. Critics said one problem with the study was that many of the women, like Brann’s aged rats, had gone years without hormone replacement, bolstering the case that timing is everything.
(Source: eurekalert.org)
Brain Mapping Reveals Neurological Basis of Decision-Making in Rats
Scientists at UC San Francisco have discovered how memory recall is linked to decision-making in rats, showing that measurable activity in one part of the brain occurs when rats in a maze are playing out memories that help them decide which way to turn. The more they play out these memories, the more likely they are to find their way correctly to the end of the maze.
In their study, reported this week in the journal Neuron, the UCSF researchers implanted electrodes directly on a region of the rat brain known as the hippocampus, which is already known to play a key role in the formation and recall of memory. This same region is active when animals are learning, and it is damaged in people who have Alzheimer’s and post-traumatic stress disorder.
The study showed that when the rats paused before an upcoming choice, sometimes the hippocampus was more active and sometimes it was less active. When it was more active it did a better job of recalling memories of places the animal could go next, and the animal was more likely to go to the right place.
“We know that considering possibilities is important for decision-making, but we haven’t really known how this happens in the brain,” said neuroscientist Loren Frank, PhD, who led the research. Frank is an associate professor of physiology and a member of the UCSF Center for Integrative Neuroscience at UCSF.
The work builds upon several years of investigations in Frank’s laboratory that have shown how activity in the hippocampus is a fundamental constituent of memory retrieval. Their recent work shows that this activity is not just about remembering the past – it is also important for thinking about the future. When the brain does a better job of thinking about future possibilities, it makes better decisions.
Next, the team wants to tease out why sometimes the hippocampus does not do a good job of playing out future options. Problems with memory and decision-making are central to age-related cognitive decline, and a deeper understanding of how this works could pave the way for interventions that make the brain work better.
Researchers Identify Possible Treatment Window for Memory Problems
Researchers have identified a possible treatment window for plaques in the brain that are thought to cause memory loss in diseases such as Alzheimer’s, according to a new study published in the February 27, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Our study suggests that plaques in the brain that are linked to a decline in memory and thinking abilities, called beta amyloid, take about 15 years to build up and then plateau,” said Clifford R. Jack, Jr., MD, with the Mayo Clinic in Rochester, Minn.
For the study, 260 people between the ages of 70 and 92 underwent two or more brain scans over an average of 1.3 years that measured plaque buildup in the brain. Of the participants, 78 percent did not have impaired thinking abilities or memory at the start of the study.
The study found that the rate of buildup accelerates initially, then slows down before plateauing at high levels. For example, lower rates of plaque buildup were found in both people who had low and high levels of the plaques at the start of the study while the rate of plaque accumulation was highest in participants with mid-range levels at the start of the study.
The study also found that the rate of buildup of plaques was more closely tied to the total amount of amyloid plaques in the brain than other risk factors, such as the level of cognitive impairment, age and the presence of the APOE gene, a gene linked to Alzheimer’s disease.
“Our results suggest that there is a long treatment window where medications may be able to help slow buildup of the amyloid plaques that are linked to cognitive decline,” said Jack. “On the other hand, trying to treat the plaque buildup after the amyloid plaque load has plateaued may not do much good.”
Scientists make older adults less forgetful in memory tests
Scientists at Baycrest Health Sciences’ Rotman Research Institute (RRI) and the University of Toronto’s Psychology Department have found compelling evidence that older adults can eliminate forgetfulness and perform as well as younger adults on memory tests.
Scientists used a distraction learning strategy to help older adults overcome age-related forgetting and boost their performance to that of younger adults. Distraction learning sounds like an oxymoron, but a growing body of science is showing that older brains are adept at processing irrelevant and relevant information in the environment, without conscious effort, to aid memory performance.
“Older brains may be be doing something very adaptive with distraction to compensate for weakening memory,” said Renée Biss, lead investigator and PhD student. “In our study we asked whether distraction can be used to foster memory-boosting rehearsal for older adults. The answer is yes!”
“To eliminate age-related forgetfulness across three consecutive memory experiments and help older adults perform like younger adults is dramatic and to our knowledge a totally unique finding,” said Lynn Hasher, senior scientist on the study and a leading authority in attention and inhibitory functioning in younger and older adults. “Poor regulation of attention by older adults may actually have some benefits for memory.”
The findings, published online in Psychological Science, ahead of print publication, have intriguing implications for designing learning strategies for the mature, older student and equipping senior-housing with relevant visual distraction cues throughout the living environment that would serve as rehearsal opportunities to remember things like an upcoming appointment or medications to take, even if the cues aren’t consciously paid attention to.
It’s Not Just Amyloid: White Matter Hyperintensities and Alzheimer’s Disease
New findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.
Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualized as white matter hyperintensities (WMHs).
The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuroimaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mildcognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.
Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits.
“White Matter Hyperintensities and Cerebral Amyloidosis” was published online in JAMA Neurology.
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)
Researchers identify potential target for age-related cognitive decline
Cognitive decline in old age is linked to decreasing production of new neurons. Scientists from the German Cancer Research Center have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals.
The hippocampus – a structure of the brain whose shape resembles that of a seahorse – is also called the “gateway” to memory. This is where information is stored and retrieved. Its performance relies on new neurons being continually formed in the hippocampus over the entire lifetime. “However, in old age, production of new neurons dramatically decreases. This is considered to be among the causes of declining memory and learning ability”, Prof. Dr. Ana Martin-Villalba, a neuroscientist, explains.
Martin-Villalba, who heads a research department at the German Cancer Research Center (DKFZ), and her team are trying to find the molecular causes for this decrease in new neuron production (neurogenesis). Neural stem cells in the hippocampus are responsible for continuous supply of new neurons. Specific molecules in the immediate environment of these stem cells determine their fate: They may remain dormant, renew themselves, or differentiate into one of two types of specialized brain cells, astrocytes or neurons. One of these factors is the Wnt signaling molecule, which promotes the formation of young neurons. However, its molecular counterpart, called Dickkopf-1, can prevent this.
"We find considerably more Dickkopf-1 protein in the brains of older mice than in those of young animals. We therefore suspected this signaling molecule to be responsible for the fact that hardly any young neurons are generated any more in old age." The scientists tested their assumption in mice whose Dickkopf-1 gene is permanently silenced. Professor Christof Niehrs had developed these animals at DKFZ. The term "Dickkopf" (from German "dick" = thick, "Kopf" = head) also goes back to Niehrs, who had found in 1998 that this signaling molecule regulates head development during embryogenesis.