Lipid and glucose levels at age 35 associated with Alzheimer's disease
Study has implications for delaying or lowering risk
March 23, 2022
Science Daily/Boston University School of Medicine
Living your best life at 35, ignoring cholesterol and glucose levels, may impact your chances of getting Alzheimer's disease (AD) later in life. According to researchers from Boston University School of Medicine (BUSM), lower HDL (high-density cholesterol) and high triglyceride levels measured in blood as early as age 35 are associated with a higher incidence of AD several decades later in life. They also found that high blood glucose measured between ages 51-60 is associated with risk of AD in the future.
"While our findings confirm other studies that linked cholesterol and glucose levels measured in blood with future risk of Alzheimer's disease, we have shown for the first time that these associations extend much earlier in life than previously thought," explains senior author Lindsay A. Farrer, PhD, chief of biomedical genetics at BUSM.
The researchers believe that although high LDL has been consistently associated with AD risk in many previous studies, the link between HDL and AD was inconclusive, perhaps because most studies examining these relationships were conducted in persons who were 55 years and older at baseline.
This study was conducted using data obtained from participants of the Framingham Heart Study who were examined in approximately four-year intervals throughout most of their adult lives. Correlations of AD with multiple known risk factors for cardiovascular disease and diabetes (including HDL, LDL, triglycerides, glucose, blood pressure, smoking, and body mass index) were measured at each exam and during three age periods during adulthood (35-50, 51-60, 61-70).
The researchers found that lower HDL (the good cholesterol) is predictive of AD in early (35-50 years) and middle (51-60 years) adulthood and that high glucose in the blood (a precursor of diabetes) during mid-adulthood is also predictive of AD "These findings show for the first time that cardiovascular risk factors, including HDL which has not been consistently reported as a strong risk factor for AD, contribute to future risk of AD starting as early as age 35," says first and corresponding authorXiaoling Zhang, MD, PhD, assistant professor of medicine at BUSM.
According to the researchers, careful management of these factors starting in early adulthood can lower one's risk of cardiovascular disease and diabetes, as well as Alzheimer's."Intervention targeting cholesterol and glucose management starting in early adulthood can help maximize cognitive health in later life," adds Farrer.
Farrer also points out, "the unique design and mission of the Framingham Heart Study, which is a multi-generation, community-based, prospective study of health that began in 1948, allowed us to link Alzheimer's to risk factors for heart disease and diabetes measured much earlier in life than possible in most other studies of cognitive decline and dementia."
https://www.sciencedaily.com/releases/2022/03/220323101236.htm
Novel heart ultrasound measures can be used to predict risk of developing dementia
March 22, 2022
Science Daily/University of Minnesota Medical School
Published in JAMA, research from the University of Minnesota assessed if there is a link between heart health and dementia.
Using echocardiography -- visual ultrasound of the heart -- the research team was able to identify novel measures that are linked to a higher dementia risk.
"Atrial myopathy, a condition characterized by abnormal left atrial function and size, is an independent risk factor for dementia," said Dr. Lin Yee Chen, director of the cardiac electrophysiology section at the U of M Medical School and M Health Fairview, and principal investigator of the NIH grant that funded this study. "In this community-based cohort study, lower left atrial function was associated with higher risk of dementia."
The study observed a cohort of 4,096 participants with an average age of 35 years. Participants were 60% women, 22% Black and 78% white. Of the cohort, there were 531 participants who developed dementia over a six year period.
When comparing the lowest to the highest quintile of left atrial function measures (reservoir strain, conduit strain, and contractile strain), the lowest quintile was significantly associated with 1.5 to 2.0-fold higher risk of developing dementia. These associations were independent of cardiovascular disease and atrial fibrillation. The research team found that the more common measures of left atrial size were not significantly associated with dementia.
"Results of this epidemiological study improve our understanding of the link between cardiovascular disease and increased risk of dementia," said Jacqueline D. Wright, Dr.P.H., a program officer in the division of cardiovascular sciences at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. "This study suggests that atrial myopathy increases risk of dementia, independently of atrial fibrillation. Further research may confirm this finding, help us to better define and diagnose atrial myopathy, and ultimately lead to improved treatments that reduce the chance of developing dementia later in life."
Researchers recommend additional studies to confirm their findings and to establish a robust definition for atrial myopathy.
https://www.sciencedaily.com/releases/2022/03/220322122557.htm
Lithium may decrease risk of developing dementia
March 17, 2022
Science Daily/University of Cambridge
Researchers have identified a link suggesting that lithium could decrease the risk of developing dementia, which affects nearly one million people in the UK.
The researchers, from the University of Cambridge, conducted a retrospective analysis of the health records of nearly 30,000 patients from Cambridgeshire and Peterborough NHS Foundation Trust. The patients were all over the age of 50 and accessed NHS mental health services between 2005 and 2019.
The analysis suggested that patients who received lithium were less likely to develop dementia than those who did not, although the overall number of patients who received lithium was small.
Their findings, reported in the journal PLoS Medicine, support the possibility that lithium could be a preventative treatment for dementia, and could be progressed to large randomised controlled trials.
Dementia is the leading cause of death in elderly Western populations, but no preventative treatments are currently available: more than 55 million people worldwide have dementia, with Alzheimer's disease the most common form.
"The number of people with dementia continues to grow, which puts huge pressure on healthcare systems," said Dr Shanquan Chen from Cambridge's Department of Psychiatry, the paper's first author. "It's been estimated that delaying the onset of dementia by just five years could reduce its prevalence and economic impact by as much as 40 percent."
Previous studies have proposed lithium as a potential treatment for those who have already been diagnosed with dementia or early cognitive impairment, but it is unclear whether it can delay or even prevent the development of dementia altogether, as these studies have been limited in size.
Lithium is a mood stabiliser usually prescribed for conditions such as bipolar affective disorder and depression. "Bipolar disorder and depression are considered to put people at increased risk of dementia, so we had to make sure to account for this in our analysis," said Chen.
Chen and his colleagues analysed data from patients who accessed mental health services from Cambridgeshire and Peterborough NHS Foundation Trust between 2005 and 2019. Patients were all over 50 years of age, received at least a one-year follow-up appointment, and had not been previously diagnosed with either mild cognitive impairment or dementia.
Of the 29,618 patients in the study cohort, 548 patients had been treated with lithium and 29,070 had not. Their mean age was just under 74 years, and approximately 40% of patients were male.
For the group that had received lithium, 53, or 9.7%, were diagnosed with dementia. For the group that had not received lithium, 3,244, or 11.2%, were diagnosed with dementia.
After controlling for factors such as smoking, other medications, and other physical and mental illnesses, lithium use was associated with a lower risk of dementia, both for short and long-term users. However, since the overall number of patients receiving lithium was small and this was an observational study, larger clinical trials would be needed to establish lithium as a potential treatment for dementia.
Another limitation of the study was the number of patients who had been diagnosed with bipolar disorder, which is normally associated with an increased risk of dementia. "We expected to find that patients with bipolar disorder were more likely to develop dementia, since that is the most common reason to be prescribed lithium, but our analysis suggested the opposite," said Chen. "It's far too early to say for sure, but it's possible that lithium might reduce the risk of dementia in people with bipolar disorder."
This paper supports others which have suggested lithium might be helpful in dementia. Further experimental medicine and clinical studies are now needed to see if lithium really is helpful in these conditions.
https://www.sciencedaily.com/releases/2022/03/220317143710.htm
Extended napping in seniors may signal dementia
Daytime sleep duration triples after Alzheimer's diagnosis
March 17, 2022
Science Daily/University of California - San Francisco
Daytime napping among older people is a normal part of aging -- but it may also foreshadow Alzheimer's disease and other dementias. And once dementia or its usual precursor, mild cognitive impairment, are diagnosed, the frequency and/or duration of napping accelerates rapidly, according to a new study.
The study, led by UC San Francisco and Harvard Medical School together with Brigham and Women's Hospital, its teaching affiliate, departs from the theory that daytime napping in older people serves merely to compensate for poor nighttime sleep. Instead, it points to work by other UCSF researchers suggesting that dementia may affect the wake-promoting neurons in key areas of the brain, the researchers state in their paper publishing March 17, 2022, in Alzheimer's and Dementia: The Journal of the Alzheimer's Association.
"We found the association between excessive daytime napping and dementia remained after adjusting for nighttime quantity and quality of sleep," said co-senior author Yue Leng, MD, PhD, of the UCSF Department of Psychiatry and Behavioral Sciences.
"This suggested that the role of daytime napping is important itself and is independent of nighttime sleep," said Leng, who partnered with Kun Hu, PhD, of Harvard Medical School, in senior-authoring the paper.
Watch-Like Devices, Annual Evaluations Used to Measure Naps, Cognition
In the study, the researchers tracked data from 1,401 seniors, who had been followed for up to 14 years by the Rush Memory and Aging Project at the Rush Alzheimer's Disease Center in Chicago. The participants, whose average age was 81 and of whom approximately three-quarters were female, wore a watch-like device that tracked mobility. Each prolonged period of non-activity from 9 a.m. to 7 p.m. was interpreted as a nap.
The device was worn every year continuously for up to 14 days, and once a year each participant underwent a battery of neuropsychological tests to evaluate cognition. At the start of the study 75.7% of participants had no cognitive impairment, while 19.5% had mild cognitive impairment and 4.1% had Alzheimer's disease.
For participants who did not develop cognitive impairment, daily daytime napping increased by an average 11 minutes per year. The rate of increase doubled after a diagnosis of mild cognitive impairment to a total of 24 minutes and nearly tripled to a total of 68 minutes after a diagnosis of Alzheimer's disease.
When the researchers looked at the 24% of participants who had normal cognition at the start of the study but developed Alzheimer's six years later, and compared them with those whose cognition remained stable, they found differences in napping habits. Participants who napped more than an hour a day had a 40% higher risk of developing Alzheimer's than those who napped less than an hour a day; and participants who napped at least once a day had a 40% higher risk of developing Alzheimer's than those who napped less than once a day.
The research confirms the results of a 2019 study, of which Leng was the first author, that found older men who napped two hours a day had higher odds of developing cognitive impairment that those who napped less than 30 minutes a day. The current study builds on these findings by evaluating both daytime napping and cognition each year, hence addressing directionality, Leng notes.
Loss of Wake-Promoting Neurons May Account for Longer Naps
According to the researchers, increase in napping may be explained by a further 2019 study, by other UCSF researchers, comparing the postmortem brains of people with Alzheimer's disease to those without cognitive impairment. Those with Alzheimer's disease were found to have fewer wake-promoting neurons in three brain regions. These neuronal changes appear to be linked to tau tangles -- a hallmark of Alzheimer's, characterized by increased activity of enzymes causing the protein to misfold and clump.
"It is plausible that our observed associations of excessive daytime napping at baseline, and increased risk for Alzheimer's disease during follow-up, may reflect the effect of Alzheimer's disease pathology at preclinical stages," the authors noted.
The study shows for the first time that napping and Alzheimer's disease "seem to be driving each other's changes in a bi-directional way," said Leng, who is also affiliated with the UCSF Weill Institute for Neurosciences. "I don't think we have enough evidence to draw conclusions about a causal relationship, that it's the napping itself that caused cognitive aging, but excessive daytime napping might be a signal of accelerated aging or cognitive aging process," she said.
"It would be very interesting for future studies to explore whether intervention of naps may help slow down age-related cognitive decline."
https://www.sciencedaily.com/releases/2022/03/220317111848.htm
Plasma biomarker screening could improve accuracy, health equity in Alzheimer’s disease diagnosis
March 17, 2022
Science Daily/Mayo Clinic
A new study focuses on RNA molecules in plasma as biomarkers for Alzheimer's disease in African Americans -- the population at greatest risk for developing Alzheimer's disease. This approach enabled researchers to pinpoint specific molecules in plasma that could serve as biomarkers to confirm a diagnosis of Alzheimer's disease in this population.
Mayo Clinic researchers have identified a new set of molecular markers in blood plasma. This discovery could lead to the development of improved diagnostic tests for Alzheimer's disease. Alzheimer's disease is the most common form of dementia, affecting 6.2 million people in the U.S.
The Mayo Clinic study, published in eBioMedicine, is the first study to focus on RNA molecules in plasma as biomarkers for Alzheimer's disease in African Americans -- the population at greatest risk for developing Alzheimer's disease. This approach enabled researchers to pinpoint specific molecules in plasma that could serve as biomarkers to confirm a diagnosis of Alzheimer's disease in this population.
The study builds on previous research that identified genetic risk factors for Alzheimer's disease and established that RNA molecules in blood plasma could potentially be used as biomarkers.
In the study, researchers examined blood plasma messenger RNA molecules in 151 African Americans diagnosed with Alzheimer's disease and 269 African Americans diagnosed as cognitively unimpaired with Clinical Dementia Rating scale scores of zero. The researchers found that when the plasma levels of six messenger RNA molecules -- encoded by genes CLU, APP, CD14, ABCA7, AKAP9 and APOE -- were accounted for in their statistical models, they improved their ability to accurately identify participants with an Alzheimer's diagnosis by 8%. Researchers explain this is an improvement, compared to statistical models that account for only the presence of known risk factors, such as age and sex, and whether the person is a carrier of the APOE-e4 allele -- a gene known to increase the risk of Alzheimer's disease.
The researchers predict this discovery could lead to more accurate Alzheimer's disease screening for everyone, particularly for the people and communities at greatest risk.
"Having a comprehensive panel of biomarkers for use in screening will help with early detection of Alzheimer's disease, and it will also contribute to intervention strategies that can delay and mitigate the onset of the disease," says Joseph Reddy, Ph.D., a Mayo Clinic quantitative health sciences researcher and first author. "This could be especially relevant for African Americans -- a population underrepresented in Alzheimer's disease research -- who were the focus of this study."
The researchers predict that this discovery could contribute to the development of more accessible, minimally invasive screening options, enabling improved disease management.
"Many screening tests for Alzheimer's disease may not be accessible to all patients due to cost or lack of availability at health care facilities in their area," says Minerva Carrasquillo, Ph.D., a Mayo Clinic neurogeneticist and senior author. "Some tests rely on complex imaging techniques, or on obtaining a sample of cerebrospinal fluid from the patient. Obtaining a plasma sample only requires a blood draw, which is a routine procedure in most clinical settings."
The researchers indicate that future research will focus on identifying additional genetic biomarkers in blood plasma that may improve the accuracy of Alzheimer's disease diagnostic tests.
https://www.sciencedaily.com/releases/2022/03/220317111843.htm
Alzheimer’s: Protective immune cells active decades before symptom onset
Boosting the brain’s defenses could help combat the disease
March 17, 2022
Science Daily/DZNE - German Center for Neurodegenerative Diseases
In individuals with a genetic predisposition to Alzheimer's disease, the immune cells of the brain -- the "microglia" -- start exerting a protective effect up to two decades before the first symptoms appear. A team from Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) and Ludwig-Maximilians-Universität (LMU) München draws this conclusion based on a study of more than 200 volunteers, which they report in the journal The Lancet Neurology. In light of their study data, the scientists consider modulating the activity of microglia to be a promising therapeutic approach. To this end, they aim to develop drugs that target a cellular receptor called TREM2.
About one percent of all people with Alzheimer's develop the disease as a result of gene mutations that can be passed on from generation to generation. As part of the international DIAN (Dominantly Inherited Alzheimer Network) observational study, DZNE and LMU München are participating in research into this genetic form of Alzheimer's disease. The DIAN study cohort includes adults who carry gene mutations that cause Alzheimer's as well as their close relatives without mutations.
Measurements Over Several Years
For the current research, the team led by molecular biologist Prof. Christian Haass and neurologist Dr. Estrella Morenas-Rodríguez analyzed how signatures of microglial activation were related to the development of certain biomarkers of Alzheimer's disease. To this end, cerebrospinal fluid and cognition were assessed over a period of several years in 248 participants of the DIAN study comprising the different stages of Alzheimer's disease. The volunteers were also examined by magnetic resonance imaging (MRI) and positron emission tomography (PET) to visualize brain shrinkage and amyloid pathology -- both are hallmarks of Alzheimer's disease.
The starting point for the research team was a protein called TREM2. "This is a receptor on the surface of microglia, but parts of it can detach and are then detectable in the cerebrospinal fluid. It is known from laboratory studies, particularly in mice but also from our earlier human studies, that levels of TREM2 in the cerebrospinal fluid are a good indicator of microglial activity. TREM2 is a kind of activity switch. As TREM2 levels increase, so do microglial protective activities," explains Christian Haass, research group leader at DZNE and professor of biochemistry at LMU München. "For a long time, it was assumed that microglia mainly cause damage in the course of Alzheimer's disease, as they can fuel chronic inflammatory processes. However, there is growing evidence from my laboratory and many others that microglia have a protective effect at least at the beginning of the disease. This hypothesis is supported by our current data."
Estrella Morenas-Rodríguez, postdoctoral researcher in the Haass team at the time of the investigation and now junior group leader at Hospital Universitario 12 de Octubre in Madrid, Spain adds: "One of the determinant points which allowed us to make our observations, and that was also a challenge, was to be able to study for the first time the increase of the TREM2 marker longitudinally. That is, we measured the marker in several samples taken from the same individuals every one or two years. With that we could better capture the development of the different processes occurring in Alzheimer´s disease than studying samples at just one time point."
Conspicuous Long in Advance
People with a genetic predisposition to Alzheimer's usually develop the disease at a similar age as their relatives with the same mutation who already experience symptoms of dementia. Based on this experience, the researchers were able to estimate the time until the onset of symptoms for all study participants individually. In doing so, they came across early signs of the disease. "We found that TREM2 levels in the cerebrospinal fluid rise as early as 21 years before the estimated onset of the disease," Haass says. "We also observed that the faster TREM2 increases over the years, the slower pathological events progress in the brain that are typical of Alzheimer's. We can infer this from biomarkers for so-called amyloid proteins and tau proteins."
The brain examinations using MRI and PET pointed in a similar direction: In study participants in whom TREM2 levels rose rapidly, deposits of amyloid proteins that are characteristic of Alzheimer's developed more slowly and brain volume declined more slowly. "Besides the relationship with a slower pathological process, one of our most important and promising findings was to see how strikingly the faster TREM2 increase correlated with a slower cognitive decline in an early stage of Alzheimer´s disease. This has important implications for treatment," Morenas-Rodríguez notes.
"We see our findings as evidence that TREM2-mediated microglial activity has a protective effect," Haass says. "In our view, microglia become active as soon as the first amyloid proteins are deposited in the brain, a process, which we call seeding. In other words, at a very early stage of Alzheimer's and that is what we and our colleagues at the DZNE-Tübingen also observe in animal models."
Approach for New Therapies
For some time now, Haass and his team have been researching drugs that specifically reinforce the protective effect of microglia. Their target is the TREM2 receptor anchored on the cell surface. "We are still in the laboratory phase. However, the current results in humans show that modulating TREM2 is a promising strategy to develop new options against Alzheimer's. Although in this particular case we studied the genetic form of the disease, we consider that our findings also apply to the so-called sporadic variant of the disease, which is far more common. Certainly, it is crucial that treatment starts as early as possible. Today's therapies all come far too late to be really effective," says Haass.
https://www.sciencedaily.com/releases/2022/03/220317094758.htm
Large study on traumatic brain injury highlights global inequality in causes and treatment
March 17, 2022
Science Daily/University of Cambridge
A large study examining the surgical management of traumatic brain injuries highlights regional inequalities in both major causes and treatment of such injuries.
Neurosurgery experts from Cambridge have led the largest ever study examining the surgical management of traumatic brain injuries, highlighting regional inequalities in both major causes and treatment of such injuries.
The Global Neurotrauma Outcomes Study, funded by the NIHR, is published in The Lancet Neurology and provides data to assist in decision making and improving outcome for patients with traumatic brain injury globally.
The paper focuses on types of cases, the way they are managed, and death rates, and was compiled using data submitted by 159 hospitals in 57 countries to a central database, which the researchers then analysed. The researchers stratified countries into four tiers (very high, high, medium, low) according to their Human Development Index (HDI), which takes account of factors like life expectancy, education, and income.
The prospective study determined that patients in the low HDI tier were often young and tended to suffer skull fractures due to assault but were classified as 'mild' traumatic brain injury (TBI).
In the medium and high HDI tiers, patients were also young, but most had moderate to severe TBI caused by a road traffic collision and extradural haematoma -- a bleed on the outside of the dura mater, the membrane covering of the brain.
In the very high tier, patients tended to be older and presented with a moderate or severe TBI associated with a fall and acute subdural haematoma -- a bleed on the inner surface of the dura mater.
Quality of care was generally less favourable in lower HDI settings, including delays to surgery and a lack of postoperative monitoring equipment and intensive care. The very high HDI tier had the highest proportion of operations in which the most senior surgeon present in the operating theatre was a fully qualified neurosurgeon, while the medium HDI tier had the lowest proportion. The study also found significant variations between hospitals in the outcome of patients.
Angelos Kolias, Consultant Neurosurgeon at Cambridge University Hospitals NHS Foundation Trust (CUH) and NIHR Global Neurotrauma Research Group associate director, said: "The results show that overall mortality is low, reflecting the life-saving nature of surgery for traumatic brain injuries. Many of these patients would have died without an operation. However, we also need to address deficits in pre-hospital management and long-term rehabilitation."
David Clark, a trainee neurosurgeon and University of Cambridge research fellow, said: "A particularly important finding is that outcome is influenced more by hospital characteristics than country of origin, which raises the possibility that changing the systems and processes of care in individual hospitals might be able to improve mortality. The paper sows the seeds for discussion and change."
The research was funded by the NIHR using UK government aid to support global health research.
Alexis Joannides, Consultant Neurosurgeon at CUH and NIHR Global Neurotrauma Research Group informatics lead, added: "The contribution of several clinicians and researchers from several hospitals across the world has been possible due to the infrastructure and collaborations supported by the NIHR.
"The database and data management process used in the study have now laid the foundation for a global registry of traumatic brain injuries that we have established to support ongoing quality improvement and research in the field of traumatic brain injury."
Peter Hutchinson, Professor of Neurosurgery at the University of Cambridge and Director of the NIHR Global Neurotrauma Research Group, said: "This is the largest study in the world looking at the surgical management of head injuries and will be of practical value to clinicians and others planning strategies for the future.
"The collaboration across such a vast number of hospitals and countries, together with the support of the World Federation of Neurosurgical Societies and continental neurosurgical societies, has been phenomenal."
https://www.sciencedaily.com/releases/2022/03/220317111915.htm
Alzheimer’s pathology, not cognitive decline, drives neuropsychiatric symptoms
Biomarkers of pathology associated with apathy, anxiety
March 16, 2022
Science Daily/Elsevier
Alzheimer's disease (AD) eventually leads to severe cognitive decline, but most affected individuals also develop distressing neuropsychiatric symptoms. These earlier effects may be more subtle and are not well understood; it remains unclear whether they arise directly from AD pathology or secondarily as psychological reactions due to the cognitive deficits. Now, a new study examines the connections between biomarkers of AD's hallmark neuropathology, cognition, and other neuropsychiatric symptoms. The study appears in Biological Psychiatry, published by Elsevier.
The researchers, led by Oskar Hansson, MD, at Lund University in Sweden, tested cerebrospinal fluid or blood plasma from 356 cognitively unimpaired older adults for levels of the proteins amyloid-beta (Ab) and tau, which are thought to contribute to AD neurotoxicity, as well as markers of neurodegeneration.
Strikingly, the presence of Ab was associated with increased anxiety and apathy. Higher levels of apathy were also related to a more rapid cognitive decline.
"Most importantly, this study signals that certain neuropsychiatric symptoms such as apathy and anxiety develop predominantly due to underlying AD-related pathology and not due to the concomitant cognitive impairment," said Maurits Johansson, MD, lead author of the study. "It seems reasonable that neuropsychiatric symptoms would arise from neuropathology just as cognitive deficits do, especially because AD ultimately affects large areas of the brain," he added.
The study did not exclude a role for cognitive impairment altogether. For example, in one of the statistical analyses, cognitive decline slightly but significantly mediated the effect of amyloid pathology on the development of apathy.
"Combined with earlier studies, our findings strengthen the proposed idea that cognitive deficits and neuropsychiatric symptoms can develop independently, yet in parallel to one another. They have a common underlying neuropathology, but to some extent they can also reinforce one another," said Professor Hansson.
"These findings could ultimately lead to more efficient study design of clinical trials for AD in that they point to neuropsychiatric symptoms as potential alternative outcome measures," concluded Professor Hansson.
John Krystal, MD, Editor of Biological Psychiatry, said of the new findings, "We are used to thinking about Alzheimer's disease from the perspective of memory impairments. This new study highlights that the earliest signs of amyloid-related pathology may be changes in mood and behavior, particularly apathy and anxiety."
https://www.sciencedaily.com/releases/2022/03/220316100426.htm
Mechanism linking type 2 diabetes to Alzheimer’s disease
March 15, 2022
Science Daily/Osaka City University
Osaka City University suggests a possible mechanism linking diabetes to Alzheimer's disease in new discovery that amyloid-β in the blood comes from periphery organs like the pancreas and liver, not only the brain, and aids in blood glucose clearance by inhibiting insulin secretion.
A research group has revealed that amyloid-β (Aβ) detected in blood is secreted from peripheral tissues (pancreas, adipose tissue, skeletal muscle, liver, etc.) that are sensitive to glucose and insulin. Also, that Aβ secreted from peripheral tissues acts as a regulator on pancreatic β-cells to suppress insulin secretion. The results of this study indicate that blood Aβ levels fluctuate significantly with diet, and special care should be taken when using blood samples as a diagnostic marker for Alzheimer's disease, such as taking blood samples during fasting.
Researchers have identified amyloid beta (Aβ) detected in blood to originate from peripheral tissues, and that the peptide acts on pancreaticβ-cells to suppress insulin secretion, thereby regulating blood glucose levels. The study, which urges us to be careful when using blood Aβ levels as a diagnostic marker for Alzheimer's disease (AD), was published in The Proceedings of the National Academy of Sciences (PNAS), the official journal of the National Academy of Sciences.
"This work was finally published after about 11 years," says Professor Takami Tomiyama of the Department of Translational Neuroscience, Osaka City University Graduate School of Medicine. "It is not only an academic discovery, but also has implications in how we diagnose AD."
Based on what is known, this study sought to explore some unknowns. First, as AD is caused by the accumulation of Aβ in the brain, it is thought that Aβ levels in the blood reflect the pathology in the brain and are currently used as a diagnostic marker. However, Aβ is generated from the amyloid precursor protein (APP) through the function of two enzymes, β- and γ-secretases, and this mechanism is expressed in many of the body's peripheral tissues, not only in the brain, causing the origin of blood Aβ to remain unknown. Second, epidemiological studies have shown type 2 diabetes to be a strong risk factor for the development of AD, yet the mechanism linking these two diseases has eluded researchers as well.
"In our previous studies on mice injected with glucose," Professor Tomiyama explains, "we showed a transient increase in glucose and insulin to peak at 15 minutes, but blood Aβ levels to peak some 30-120 minutes later." In addition, previous studies have shown the oral administration of glucose to increase blood Aβ levels in patients with AD. These findings led the professor and his research team to explore the hypothesis that blood Aβ is secreted from peripheral tissues (pancreas, adipose tissue, skeletal muscle, liver, etc.) and it may contribute to the metabolism of glucose and insulin.
First, they examined the effects of glucose and insulin on blood Aβ levels of mice fasted for 16 hours. Collected blood samples from the tail vein at 0, 15, 30, 45, 60, 120, and 180 min intervals after the injection showed a transient increase in glucose, insulin, and Aβ, confirming previous studies.
Next, they explored the effect of Aβ on blood insulin levels by administering Aβ and glucose to fasted mice that cannot produce Aβ, called APP knock out mice. Measuring insulin in blood samples over time found that Aβ suppressed the glucose-stimulated rise in insulin.
Given that blood Aβ levels changed immediately upon introduction of glucose and insulin, the team focused on the mice pancreas, adipose tissue, skeletal muscle, liver, and kidneys to determine the origin of blood Aβ. They added glucose and insulin to isolated live peripheral tissues and measured the secreted Aβ. Results showed that Aβ was secreted from the pancreas upon glucose stimulation and from adipose tissue, skeletal muscle, and liver upon insulin stimulation. The kidneys, which is not involved in glucose or insulin metabolism, did not secrete Aβ upon either stimulus. They also found that when glucose and Aβ were added to pancreas tissue, levels of secreted insulin were suppressed.
Now that the origin of blood Aβ had been clarified, the team wanted to localize Aβ in the periphery tissues studied. "This would elucidate the cells involved with Aβ," adds Professor Tomiyama. "In addition to providing further validation to our findings, this would give us a more detailed picture from which we could draw conclusions to possible mechanisms connecting type 2 diabetes and AD."
Using immunohistochemistry to exploit the fact that antibodies bind to certain proteins, the team started with the pancreas tissue, detecting Aβonly in insulin (β cells). The team also found the β cells of mice with glucose injections to have less immunoreactions to Aβand insulin, suggesting during periods of fast, Aβ and insulin are stored in β cells and then released into circulation when stimulated with glucose. Similarly, tissue sections of each insulin-targeted organ were prepared and immunostained for Aβ and the bioactive substances specific to each tissue, called organokines. Aβ was found with the organokines of all the organ tissues tested, with less immunoreactions when stimulated with insulin.
"Our findings suggest that Aβ and organokines are stored during periods of fast and released into circulation when stimulated with insulin," adds Prof. Tomiyama. "A comprehensive understanding of the organokine action of peripheral Aβ is something we hope to develop in future work."
In addition to an explanation for the origin of Aβ in the blood, the research findings suggest a mechanism by which type 2 diabetes is a strong risk factor for the development of AD. In diabetes, Aβ levels in the blood are constantly elevated due to high levels of glucose and insulin. This inhibits Aβ to leave the brain to the periphery (transport through the blood-brain barrier and by body fluid flow through the brain parenchyma called the glymphatic system), causing Aβ to accumulate in the brain and develop into AD.
"Other more practical suggestions can be gleaned from this study," concludes Prof. Tomiyama, "our data suggest that as blood Aβ levels fluctuate significantly with diet, special care should be taken when diagnosing AD with blood Aβ."
https://www.sciencedaily.com/releases/2022/03/220315095012.htm
Cognitive decline key factor in predicting life expectancy in Alzheimer’s disease
March 14, 2022
Science Daily/UT Southwestern Medical Center
Cognitive decline is the biggest factor in determining how long patients with Alzheimer's disease will live after being diagnosed, according to a new study from researchers at UT Southwestern. The findings, published in the Journal of Alzheimer's Disease, are a first step that could help health care providers provide reliable prediction and planning assistance for patients with Alzheimer's disease and their families.
Using a National Alzheimer's Coordinating Center dataset on 764 autopsy-confirmed cases, C. Munro Cullum, Ph.D., Professor of Psychiatry, Neurology, and Neurological Surgery, and first author Jeffrey Schaffert, Ph.D., a postdoctoral fellow in clinical neuropsychology at UT Southwestern, identified seven factors that helped predict life expectancy variances among participants. These factors are the most predictive of how many years of life remain after diagnosis.
"Life expectancy for patients with Alzheimer's disease typically ranges from three to 12 years but can be longer in some cases. Families are anxious to know what to expect and how to best plan for the time ahead in terms of finances, family caregiving, and how they want to live out their lives," said Dr. Cullum, a neuropsychologist Investigator in the Peter O'Donnell Jr. Brain Institute who specializes in cognitive assessment. "We're trying to get them better answers."
Of the many variables studied, performance deficiencies on a brief cognitive screening test that focuses on orientation was the most significant predictor, accounting for about 20% of the variance in life expectancy. This was followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings.
"We found that beyond global cognitive function, patients who were older, non-Hispanic, male, and who had more motor and psychiatric symptoms had a significantly shorter life expectancy," Dr. Schaffert said.
The data was drawn from clinical records and autopsy reports on patients who died with Alzheimer's disease between 2005 and 2015. Alzheimer's disease was confirmed by traditional abnormalities observed in brain autopsy specimens, including the presence of abnormal protein aggregation. Life expectancy in the study group ranged from one month to 131 months after diagnosis, and most were diagnosed on their first visit.
Dr. Schaffert explained that past studies have focused on only a few of the 21 predictors identified for life expectancy. In this case, researchers had a complete dataset for 14 variables in this group, the largest to date. Moreover, past studies have not been autopsy-based, thereby confounding results with data from other forms of dementia that mimic Alzheimer's disease.
The researchers caution that prediction of life expectancy is complex and influenced by many factors. While the cognitive test used in the study was a relatively strong predictor, they plan to follow up using more sensitive measures of memory and other specific cognitive abilities as predictors and probe how the rate of decline in cognition may track with life expectancy. They also hope to expand the population base.
"This dataset was largely derived from well-educated white patients who donated their brains to research. We would like to extend this work to better reflect our more diverse patient population," Dr. Cullum said.
https://www.sciencedaily.com/releases/2022/03/220314181451.htm
Physical activity may protect your brain as you age
Even just a few more steps a day benefits cognitive function
March 8, 2022
Science Daily/University of Georgia
We all know we should exercise and eat healthy. But doing that isn't just good for maintaining your figure as you age.
New research from the University of Georgia shows that physical activity could help protect your cognitive abilities as you age. And it doesn't have to be intense exercise to make an impact.
"This finding isn't saying, 'If you're older, you need to go out there and start running marathons,'" said Marissa Gogniat, lead author of the study and a recent doctoral graduate in psychology from the Franklin College of Arts and Sciences. "This is saying if you get more steps, if you're moving around your environment a little bit more, that can be helpful to your brain health and keep you more independent as you age."
Exercise improves brain function
Published in Sport Sciences for Health, the study followed 51 older adults, tracking their physical activity and fitness measurements. The participants performed tests specifically designed to measure cognitive functioning and underwent MRIs to assess brain functioning.
They also wore a device that measured the intensity of the wearer's physical activity, number of steps taken and distance covered. The researchers assessed fitness through a six-minute walking test, during which participants walked as quickly as they could to cover the most distance possible within the time limit.
"We've always been told it's good to exercise, but I think this is some evidence that exercise can actually change your brain," Gogniat said. "And that impacts the way you're able to function in your daily life."
Brain networks improve with physical activity
The brain is made up of a bunch of distinct networks. Those networks are in constant communication, sending information to each other.
But different parts of the brain are active at different times. The network that is active when the body is at rest, for example, flips off when a person starts trying to complete a task. At that time, another network kicks on.
While one of these networks is active, the other should be shut off. If it's not, that's a sign that a person's brain isn't functioning as well as it should be.
These networks are the key to being able to perform basic tasks in daily life, such as remembering important information and exhibiting self-control. But as people age, these tasks often become more difficult.
This study was the first to examine how these networks interact with physical activity and fitness to impact how the brain functions.
"This paper is exciting because it gives us some evidence that when people whose brain networks aren't functioning optimally engage in physical activity, we see improvement in their executive function and their independence," Gogniat said. "We're not saying you need to radically change your life.
"Maybe just take the stairs on the way to work. Stand up and walk around a little bit more. That's where you get the most bang for your buck, not crazy, high-intensity exercise."
https://www.sciencedaily.com/releases/2022/03/220308155637.htm
Higher education and language skills may help ward off dementia
March 3, 2022
Science Daily/University of Waterloo
New research has found that people with mild cognitive impairment may not inevitably develop dementia and, in fact, having higher education and advanced language skills more than doubles their chances of returning to normal.
The study, led by researchers at the University of Waterloo, may reassure those with mild cognitive impairment as it contradicts a common assumption that the condition is simply an early stage of dementia. People with mild cognitive impairment show signs of cognitive decline, but not enough to prevent them from performing typical daily tasks. They have been considered at higher risk of progressing to the more severe cognitive decline seen in dementia.
"Possessing high cognitive reserve -- based on education, high academic grades, and written language skills -- may predict what happens years after someone receives a diagnosis of mild cognitive impairment," said Suzanne Tyas, a professor in the School of Public Health Sciences at Waterloo and lead author. "Even after considering age and genetics -- established risk factors for dementia -- we found that higher levels of education more than doubled the chances that people with mild cognitive impairment would return to normal cognition instead of progressing to dementia."
The study also found that language skills, whether reflected in high grades in English in school or in strong writing that was grammatically complex and full of ideas, were also protective.
The researchers discovered that almost one-third of 472 women diagnosed with mild cognitive impairment reverted to normal cognition at least once over an average of eight-and-a-half years following their diagnosis, with more than 80 per cent of them never developing dementia.
Almost another third of the total number progressed to dementia without ever reverting to normal cognition, while three per cent stayed in the mild cognitive impairment stage, and 36 per cent died. None of the participants reverted from dementia to mild cognitive impairment.
The researchers also highlighted that reverse transitions are much more common than progressing to dementia in relatively younger individuals who didn't carry a certain genetic risk factor and had high levels of education and language skills.
"We can't do much about age and genetics, so it's encouraging that our findings show that there are other ways to reduce the risk of dementia, such as building cognitive reserve through education and language skills earlier in life," Tyas said.
The study's findings have implications for treatment and research in people with mild cognitive impairment.
"If individuals with higher cognitive reserve are more likely to improve even without treatment, then this needs to be taken into consideration when recruiting participants for clinical trials of prospective treatments and when interpreting the results of these trials," Tyas said, adding there's no cure for most causes of dementia, so prevention is key.
For the analysis, researchers used complex modelling with data drawn from a longitudinal study called the Nun Study, which looked at older, highly educated religious sisters. The participants were mostly homogeneous, with similar socioeconomic status and marital and reproductive history, strengthening the conclusions of this work.
https://www.sciencedaily.com/releases/2022/03/220303095634.htm
Blood pressure medications impact brain function
March 2, 2022
Science Daily/University of Minnesota Medical School
Published in Science, University of Minnesota Medical School researchers found that blood pressure medications have an unanticipated effect on the brain.
The research team discovered that drugs used to treat blood pressure unexpectedly increase the effect of opioids that the brain naturally produces. This can fine-tune the function of a specific brain circuit and counteract the addictive properties of opiates like fentanyl, which are used to treat pain.
"Our findings suggest a new strategy to boost opioid signaling in the brain in a way that is protective and beneficial, with a very low risk of dependence or addiction," said Patrick Rothwell, PhD, an assistant professor of neuroscience at the U of M Medical School and Medical Discovery Team on Addiction.
The study focused on angiotensin-converting enzyme (ACE), which has long been known to regulate blood pressure. However, little is known about the function of ACE in the brain.
Based on the study findings, Rothwell recommends further research on ACE inhibitors, a safe class of drugs used to control blood pressure. ACE inhibitors have the potential to be redesigned to treat brain conditions.
This research was funded by Minnesota's Discovery, Research, and Innovation Economy (MnDRIVE) initiative, and the National Institute on Drug Abuse. The project was led by Brian Trieu, an MD/PhD candidate working in the Rothwell lab.
https://www.sciencedaily.com/releases/2022/03/220302185942.htm
Physical fitness linked to lower risk of Alzheimer’s disease
February 28, 2022
Science Daily/American Academy of Neurology
People who are more physically fit are less likely to develop Alzheimer's disease than people who are less physically fit, according to a preliminary study released today, February 27, 2022, that will be presented at the American Academy of Neurology's 74th Annual Meeting being held in person in Seattle, April 2 to 7, 2022 and virtually, April 24 to 26, 2022.
"One exciting finding of this study is that as people's fitness improved, their risk of Alzheimer's disease decreased -- it was not an all-or-nothing proposition," said study author Edward Zamrini, MD, of the Washington VA Medical Center in Washington, D.C., and a member of the American Academy of Neurology. "So people can work toward making incremental changes and improvements in their physical fitness and hopefully that will be associated with a related decrease in their risk of Alzheimer's years later."
The study involved 649,605 military veterans in the Veterans Health Administration database with an average age of 61 who were followed for an average of nine years. They did not have Alzheimer's disease at the start of the study.
Researchers determined participants' cardiorespiratory fitness. Cardiorespiratory fitness is a measure of how well your body transports oxygen to your muscles, and how well your muscles are able to absorb oxygen during exercise.
The participants were divided into five groups, from least fit to most fit. Fitness levels were determined by how well participants did on a treadmill test. This test measures exercise capacity, the highest amount of physical exertion a person can sustain. For people who are middle-aged and older, the highest level of fitness can be achieved by walking briskly most days of the week, for two and a half hours or more per week.
The group with the lowest level of fitness developed Alzheimer's at a rate of 9.5 cases per 1,000 person-years, compared to 6.4 cases per 1,000 person-years for the most fit group. Person-years take into account the number of people in a study as well as the amount of time spent in the study. The case rate decreased as the level of fitness increased, with a rate of 8.5 for the second least fit group, 7.4 for the middle group and 7.2 for the second most fit group.
When researchers adjusted for other factors that could affect risk of Alzheimer's disease, they found that the people in the most fit group were 33% less likely to develop Alzheimer's disease than those in the least fit group. The second most fit group was 26% less likely to develop the disease, while the middle group was 20% less likely and those in the second least fit group were 13% less likely to develop the disease than those in the least fit group.
"The idea that you can reduce your risk for Alzheimer's disease by simply increasing your activity is very promising, especially since there are no adequate treatments to prevent or stop the progression of the disease," Zamrini said. "We hope to develop a simple scale that can be individualized so people can see the benefits that even incremental improvements in fitness can deliver."
A limitation of the study was participants were mostly white men so results may not be generalizable to other populations.
The study was supported by the National Institute on Aging, the National Institutes of Health, the U.S. Department of Veterans Affairs, the Washington D.C. VA Medical Center and George Washington University.
https://www.sciencedaily.com/releases/2022/02/220228125736.htm
Depression and Alzheimer’s disease share genetic roots
February 17, 2022
Science Daily/Elsevier
Epidemiological data have long linked depression with Alzheimer's disease (AD), a neurodegenerative disease characterized by progressive dementia that affects nearly 6 million Americans. Now, a new study identifies common genetic factors in both depression and AD. Importantly, the researchers found that depression played a causal role in AD development, and those with worse depression experienced a faster decline in memory. The study appears in Biological Psychiatry, published by Elsevier.
Co-senior author Aliza Wingo, MD, of Emory University School of Medicine, Atlanta, USA, said of the work, "It raises the possibility that there are genes that contribute to both illnesses. While the shared genetic basis is small, the findings suggest a potential causal role of depression on dementia."
The authors performed a genome-wide association study (GWAS), a technique that scans the entire genome for areas of commonality associated with particular conditions. The GWAS identified 28 brain proteins and 75 transcripts -- the messages that encode proteins -- that were associated with depression. Among those, 46 transcripts and 7 proteins were also associated with symptoms of AD. The data suggest a shared genetic basis for the two diseases, which may drive the increased risk for AD associated with depression.
Although previous studies had examined AD and depression using GWAS, the current work was made more powerful by using larger, newly available data sets that revealed more detailed information.
"This study reveals a relationship between depression and Alzheimer's disease and related dementia at the genetic level," said co-senior author Thomas Wingo, MD. "This is important because it may explain, at least in part, the well-established epidemiologic association between depression and higher risk for dementia."
Dr. A. Wingo added, "This relationship raises the question of whether treatment of depression can mitigate the risk for dementia. We identified genes that may explain the relationship between depression and dementia here that merit further study. Such genes may be important treatment targets for both depression and reduction of dementia risk."
"The costs of ineffectively treated depression continue to mount. There has been increasing evidence that major depressive disorder increases the risk for Alzheimer's disease, but little insight into this relationship," John Krystal, MD, Editor of Biological Psychiatry, said. "This innovative study, which links genetic risk mechanisms to molecular changes in the brain, provides the clearest link to date supporting the hypothesis that depression plays a causal role in the biology of Alzheimer's disease."
This does not mean that if one has an episode of depression that dementia is an inevitable result. Instead, it suggests that ineffectively treated depression may aggravate the biology of Alzheimer's disease, potentially hastening the onset of symptoms and increasing the rate of functional decline."
https://www.sciencedaily.com/releases/2022/02/220217122344.htm
Exercise can help older adults retain their memories
Pooling data from dozens of experiments let researchers show whose brains benefit the most from exercise
February 17, 2022
Science Daily/University of Pittsburgh
Conducting a meta-analysis of 3,000 patients over 36 studies (carefully vetted from more than 1,200 studies in all), psychologists were able to find that specific exercise helps episodic memory -- 3 times a week for 4 months, with greater improvements among those who are age 55 to 68 years.
We all know exercise is good for us, but that still leaves plenty of questions. How much exercise? Who benefits the most? And when in our lives? New research led by University of Pittsburgh psychologists pools data from dozens of studies to answer these questions, showing that older adults may be able to prevent declines in a certain kind of memory by sticking to regular exercise.
"Everyone always asks, 'How much should I be exercising? What's the bare minimum to see improvement?' " said lead author Sarah Aghjayan, a Clinical and Biological Health Psychology PhD student in the Kenneth P. Dietrich School of Arts and Sciences. "From our study, it seems like exercising about three times a week for at least four months is how much you need to reap the benefits in episodic memory."
Episodic memory is the kind that deals with events that happened to you in the past. It's also one of the first to decline with age. "I usually like to talk about the first time you got behind the wheel of a car," said Aghjayan. "So you might remember where you were, how old you were, who was in the passenger seat explaining things to you, that feeling of excitement."
Exercise that gets the heart pumping has shown promise in increasing brain health, and experiments in mice show that it improves memory -- but studies looking at the same link in humans have come out mixed.
Seeking clarity in the muddy waters of the scientific literature, the team pored over 1,279 studies, eventually narrowing them down to just 36 that met specific criteria. Then they used specialized software and no small number of Excel spreadsheets to transform the data info a form where the different studies could be directly compared.
That work paid off when they found that pooling together those 36 studies was enough to show that for older adults, exercise can indeed benefit their memory. The team, including Aghjayan's advisor Kirk Erickson in the Department of Psychology and other researchers from Pitt, Carnegie Mellon University and the University of Iowa, published their results in the journal Communications Medicine on Feb. 17.
Past analyses looking at connections between exercise and memory didn't find one, but Aghjayan and her team took several extra steps to give them the best chance of finding a link if one did exist. They limited their search to particular groups and age brackets as well as a specific kind of rigorous experimental setup. Another key was focusing specifically on episodic memory, which is supported by a part of the brain that's known to benefit from exercise.
"When we combine and merge all this data, it allows us to examine almost 3,000 participants," Aghjayan said. "Each individual study is very important: They all contribute to science in a meaningful way." Individual studies, however, may fail to find patterns that actually exist because of a lack of resources to run a big enough experiment. The studies individually couldn't find a link between exercise and memory -- it took looking at the whole body of research to bring the pattern into focus.
With that much larger pool of participants, the team was able to show a link between exercise and episodic memory, but also was able to start to answer more specific questions about who benefits and how.
"We found that there were greater improvements in memory among those who are age 55 to 68 years compared to those who are 69 to 85 years old -- so intervening earlier is better," Aghjayan said. The team also found the greatest effects of exercise in those who hadn't yet experienced any cognitive decline, and in studies where participants exercised consistently several times a week.
There are still questions left to be answered. The team's analysis couldn't answer how the intensity of exercise affects the memory benefits, and there's plenty to learn about the mechanism behind the link. But the implications for public health are clear: Exercise is an accessible way older adults can stave off memory declines, benefiting themselves, their caretakers and the healthcare system, Aghjayan said.
"You just need a good pair of walking shoes, and you can get out there and move your body."
https://www.sciencedaily.com/releases/2022/02/220217090610.htm
Lifetime of knowledge can clutter memories of older adults
February 11, 2022
Science Daily/Cell Press
When a person tries to access a memory, their brain quickly sifts through everything stored in it to find the relevant information. But as we age, many of us have difficulty retrieving memories. In a review publishing in the journal Trends in Cognitive Sciences on February 11, researchers propose an explanation for why this might be happening: the brains of older adults allocate more space to accumulated knowledge and have more material to navigate when attempting to access memories. While this wealth of prior knowledge can make memory retrieval challenging, the researchers say it has its upsides -- this life experience can aid with creativity and decision-making.
Researchers Tarek Amer (@tarekamerphd) of Columbia University and Harvard University, Jordana Wynn (@jordwynn) of Harvard University, and Lynn Hasher of the University of Toronto looked at several behavioral and neuroimaging studies, which show that older adults have difficulty suppressing information that is no longer relevant and that when searching for a specific memory, they often retrieve other, irrelevant memories along with it. The studies also showed that when given a cognitive task, older adults rely more heavily on previous knowledge than younger adults do.
While the researchers focus primarily on the difficulties that these cluttered memories may pose, they also highlight a few situations in which these crowded memoryscapes may be useful. "Evidence suggests that older adults show preserved, and at times enhanced, creativity as a function of enriched memories," the researchers write. They further hypothesize that older adults may be well served by their prior knowledge when it comes to decision-making, where they can pull on their accumulated wisdom.
With continued study and increased understanding of how memory works in older adults, researchers are hopeful that they may be able to find new ways to help them. They write, "It is possible that the increased binding and richer encodings of older adults can even be leveraged to improve older adults' learning and memory."
https://www.sciencedaily.com/releases/2022/02/220211111852.htm
Lifetime of knowledge can clutter memories of older adults
February 11, 2022
Science Daily/Cell Press
When a person tries to access a memory, their brain quickly sifts through everything stored in it to find the relevant information. But as we age, many of us have difficulty retrieving memories. In a review publishing in the journal Trends in Cognitive Sciences on February 11, researchers propose an explanation for why this might be happening: the brains of older adults allocate more space to accumulated knowledge and have more material to navigate when attempting to access memories. While this wealth of prior knowledge can make memory retrieval challenging, the researchers say it has its upsides -- this life experience can aid with creativity and decision-making.
Researchers Tarek Amer (@tarekamerphd) of Columbia University and Harvard University, Jordana Wynn (@jordwynn) of Harvard University, and Lynn Hasher of the University of Toronto looked at several behavioral and neuroimaging studies, which show that older adults have difficulty suppressing information that is no longer relevant and that when searching for a specific memory, they often retrieve other, irrelevant memories along with it. The studies also showed that when given a cognitive task, older adults rely more heavily on previous knowledge than younger adults do.
While the researchers focus primarily on the difficulties that these cluttered memories may pose, they also highlight a few situations in which these crowded memoryscapes may be useful. "Evidence suggests that older adults show preserved, and at times enhanced, creativity as a function of enriched memories," the researchers write. They further hypothesize that older adults may be well served by their prior knowledge when it comes to decision-making, where they can pull on their accumulated wisdom.
With continued study and increased understanding of how memory works in older adults, researchers are hopeful that they may be able to find new ways to help them. They write, "It is possible that the increased binding and richer encodings of older adults can even be leveraged to improve older adults' learning and memory."
https://www.sciencedaily.com/releases/2022/02/220211111852.htm
Clearance of protein linked to Alzheimer's controlled by circadian cycle
Ability of immune system to destroy Alzheimer's-related protein oscillates with daily circadian rhythm
February 10, 2022
Science Daily/Rensselaer Polytechnic Institute
The brain's ability to clear a protein closely linked to Alzheimer's disease is tied to our circadian cycle, according to research published today in PLOS Genetics. The research underscores the importance of healthy sleep habits in preventing the protein Amyloid-Beta 42 (AB42) from forming clumps in the brain, and opens a path to potential Alzheimer's therapies.
"Circadian regulation of immune cells plays a role in the intricate relationship between the circadian clock and Alzheimer's disease," said Jennifer Hurley, an expert in circadian rhythms, and associate professor of biological science at Rensselaer Polytechnic Institute. "This tells us a healthy sleep pattern might be important to alleviate some of the symptoms in Alzheimer's disease, and this beneficial effect might be imparted by an immune cell type called macrophages/microglia."
The research was conducted at the Rensselaer Center for Biotechnology and Interdisciplinary Studies, which has a focus on neurodegenerative disease. Dr. Hurley worked with Rensselaer professors Robert Linhardt, a glycans expert and inventor of synthetic heparin, and Chunyu Wang, whose ongoing research has detailed several mechanisms in the production and spread of proteins implicated in Alzheimer's.
"This insight reveals a new mechanism and path to treatment of neurodegenerative diseases like Alzheimer's through an interdisciplinary approach, and is emblematic of the CBIS strength in research and discovery and provides a new angle to human health and well-being," said Deepak Vashishth, director of the CBIS.
The circadian system is composed of a core set of clock proteins that anticipate the day/night cycle by causing daily oscillations in the levels of enzymes and hormones, ultimately affecting physiological parameters such as body temperature and the immune response. Disruption of the circadian system is increasingly associated with diseases like diabetes, cancer, and Alzheimer's.
A telltale sign of Alzheimer's disease is plaques, extracellular clumps of AB42 in the brain. Macrophages (referred to as microglia when they reside in the brain), which are immune cells that seek and destroy unwanted material, clear AB42 from the brain by ingesting it in a process called phagocytosis. In earlier research, Dr. Hurley and collaborators at the Royal College of Surgeons in Ireland investigated circadian control of macrophages, amassing an exhaustive dataset that made it possible to see which macrophage RNA and proteins oscillate with a circadian rhythm. The researchers noticed oscillations in enzymes that help to make two proteins on the macrophage cell surface -- heparan sulfate proteoglycan and chondroitin sulfate proteoglycan- both of which are known to play a role in regulating clearance of AB42.
Could these cell surface proteoglycans be a link between the circadian system and Alzheimer's? In a series of elegant experiments testing this hypothesis, the team established that the amount of AB42 ingested by healthy macrophages oscillates with a daily circadian rhythm. That pattern did not occur in macrophages without a circadian clock. They also measured daily oscillations in the levels of heparan sulfate proteoglycans and chondroitin sulfate proteoglycans produced on the surface of macrophage cells with healthy circadian cycles. Peak AB42 clearance occurred as production of surface cell proteoglycans was at its lowest level, and removal of these proteoglycans increased ingestion, which suggests that the proteoglycans inhibit AB42 clearance.
"What's clear is that this is all timed by the circadian clock," said Dr. Hurley. "When there's a lot of these cell surface proteoglycans, the macrophages don't ingest the AB42. We're not certain why that would be, but there is definitely a relationship."
That relationship could be used to develop therapies that would encourage greater AB42 clearance, perhaps by boosting the amplitude of daily oscillations, which tend to diminish as we age.
"In theory, if we could boost that rhythm, perhaps we could increase the clearance of AB42 and prevent damage to the brain," said Dr. Hurley.
https://www.sciencedaily.com/releases/2022/02/220210154215.htm
Stargazing in the brain: 'Star-like' cells display unique activity patterns
February 9, 2022
Science Daily/Okinawa Institute of Science and Technology (OIST) Graduate University
The way we experience the world occurs due to complex and intricate interactions between neurons in the brain. Now, a study, published 9th February 2022 in Science Advances, suggests that astrocytes -- star-shaped, non-neuronal cells in the brain -- might also play an important role in processing information, and perhaps even memory.
Using advanced imaging and analysis techniques, researchers from the Okinawa Institute of Science and Technology Graduate University (OIST) recorded signaling within single astrocytes at a previously unseen level of detail and speed in the brains of awake mice.
Their findings, including ultra-fast signals on par with those seen in neurons and patterns of signaling activity that correspond to different behaviors, suggest that astrocytes may play a crucial role in many functions of our brain, including how we think, move, and learn.
"If these implications are true, it will fundamentally transform how we think about neuroscience, and the way the brain works," said first author Dr. Leonidas Georgiou, a former PhD student in the Optical Neuroimaging Unit at OIST.
When we picture our brain, we typically imagine a messy tangle of long, wire-like neurons that send electrical signals to each other across different regions of the brain. But neurons only make up half the cells in our brain. Crammed into all the remaining space between the jumble of neurons are many other types of brain cells, including astrocytes.
"Compared to neurons, astrocytes have received very little attention. It was thought that astrocytes are just helper cells, supplying the neurons with nutrients and removing their waste," said Professor Bernd Kuhn, senior author and head of the Optical Neuroimaging Unit.
But in recent years, there's been increasing amounts of evidence that astrocytes can listen to chemical messages sent between neurons at synapses, and can respond with their own signals, providing an extra layer of complexity to how our brain receives and responds to information.
Still, the previously detected signals in astrocytes were about ten times slower than signals seen in neurons, with scientists therefore believing the cells were too slow for information processing.
However, by developing a new toolkit that allows the study of astrocyte activity in awake mice with unprecedented detail, the researchers at OIST showed for the first time that astrocytes generate signals in vivo which are as fast as that of neurons, lasting fewer than 300 milliseconds.
Their toolkit relied on a new discovery: that a virus regularly used for gene therapy could "jump" from neurons to connected astrocytes. The scientists used an adeno-associated virus that contained a gene that makes infected cells fluoresce. The fluorescence increases in intensity in the presence of calcium -- an important indicator of signal activity within living cells.
Once labelled, the research team were able to use a powerful, homebuilt microscope to pinpoint and image a single astrocyte, over multiple days for up to an hour at a time, while the mouse was awake and moving.
The scientists then used an advanced computer program to analyze the recorded images, allowing them to detect the never-before-seen ultra-fast flashes of calcium signals, and evaluate signal patterns in an unbiased way.
They found that sensory stimulation, by tickling the whiskers, resulted in very little calcium signaling, while certain behaviors, like running or walking, resulted in high levels of activity.
The scientists also realized that there were certain areas in the astrocyte, or hotspots, where levels of activity were higher.
"These hotspot maps are like fingerprints -- for a specific behavior, they are stable over time, remaining the same over a period of days, and unique to each astrocyte," said Dr. Georgiou.
Even more surprisingly, the team noticed that different behaviors corresponded to unique hotspot patterns.
"So, when the mouse is resting, you see one pattern. And then when the mouse is running, you see a different pattern," said Prof. Kuhn.
One hypothesis suggested by Prof. Kuhn is that these hotspot maps could represent memory engrams -- a pattern that represents a specific behavior or a memory. Different neuron networks are active during specific behaviors or when learning and recalling information, which could also change the activity of nearby astrocytes. Memory engrams are still theoretical, and highly controversial, he acknowledged.
"We still don't know how memories are stored in a brain, but it's incredible to think that it could involve astrocytes," he said. "It's likely too good to be true, but it's an exciting hypothesis to follow up on."
https://www.sciencedaily.com/releases/2022/02/220209154813.htm