Long-term memory performance depends upon gating system

Suppression of genetic switch boosts hardwired memory in Drosophila

January 13, 2020

Science Daily/Scripps Research Institute

Why do we remember some experiences for our entire lives but quickly forget others? The brain is constantly deciding which events are important enough for long-term storage. A new study sheds light on one element of that process.

Storing and retrieving memories is among the most important tasks our intricate brains must perform, yet how that happens at a molecular level remains incompletely understood. A new study from the lab of Neuroscience Professor Ronald Davis, PhD, at Scripps Research, Florida, sheds light on one element of that memory storage process, namely the storage and retrieval of a type of hardwired long-term memory.

The Davis team found that moving memories to long-term storage involves the interplay of multiple genes, a known group whose activity must be upregulated, and, unexpectedly, another gatekeeping gene set, Ras, and its downstream connecting molecules, which are down-regulated. If either Ras or its downstream connector Raf are silenced, long-term memory storage is eliminated, the team writes in the Proceedings of the National Academies of Sciences, published the week of Jan. 13.

The type of memory they studied, ironically has a rather difficult-to-remember name: "protein-synthesis dependent long-term memory," or PSD-LTM for short. To study how it and other types of memory form, scientists rely upon the fruit fly, Drosophila melanogaster, as a model organism. The genetic underpinnings of memory storage are mostly conserved across species types, Davis explains.

To assess how the flies' memory consolidation process works at a molecular level, they used a process called RNA interference to lower expression of several candidate genes in several areas of the fly brain. Doing so with both the Ras gene and its downstream molecule Raf in the fly brain's mushroom body, its memory-storage area, had a two-pronged effect. It dramatically enhanced intermediate-term memories while completely eliminating PSD long-term memory of an aversive experience, Davis says.

The team's experiments involved exposing flies to certain odors in one section of a glass tube while simultaneously administering a foot-shock. Flies' subsequent avoidant behavior on exposure to that odor indicated their recollection of the unpleasant shock. Regardless of how many times the flies were "trained," lowering expression of Ras and Raf reduced their PSD long-term memory performance, explains first author Nathaniel Noyes, PhD, a research associate in the Davis lab.

While the Ras enzyme, Ras85D, was already known for its roles in organ development and cancer, the studies showed that in the adult brain, it apparently plays memory gatekeeper, helping direct whether experiences should be remembered as intermediate memory that dissipates after a time, or as long-term "protein-synthesis dependent" memory that persists.

Gating off the memory from the intermediate storage process shifted it over to PSD long-term memory storage, indicates that it's an either-or situation. Intermediate storage appears to be the fly brain's preferential, default pathway, Noyes says. He expects that the neurotransmitter dopamine will prove to play a key signaling role.

"We believe that dopamine signals to the brain that this memory is important enough to be stored long-term. We speculate that Ras and Raf receive this dopamine signal and thereby block intermediate memory and promote PSD long-term memory," Noyes says.

How this "intermediate" memory system works in humans requires further study as well, he adds.

"It's becoming apparent that many of the same genes involved in intermediate memory storage also play a role in mammalian memory and plasticity," he notes.

https://www.sciencedaily.com/releases/2020/01/200113153330.htm

Environmental light triggers production of memory proteins in fruit flies

January 13, 2020

Science Daily/Society for Neuroscience

Maintaining long-term memories requires environmental light, according to research in fruit flies recently published in JNeurosci.

Memories begin in a temporary form, which are converted into long term memories as protein expression and brain circuits change. But, long term memories require active maintenance in order to survive the changing molecular landscape of the brain. Previous research indicates exposure to different colors of light alters memory function in humans and animals, but the role of natural lighting conditions in memory maintenance remains unknown.

Inami et al. explored this question by testing the ability of male fruit flies to learn that their proposal is not accepted by females through their courtship toward unreceptive females. After the learning period, the male fruit flies were either exposed to constant darkness, constant light, or a 12-hour light/dark cycle. The flies experiencing a light/dark cycle recognized the ready-to-mate females for five days, whereas flies in constant darkness couldn't maintain the memory. The researchers found environmental light exposure activates light-sensitive neurons, triggering the production of memory maintenance proteins. Darkness during the learning period did not affect memory formation, indicating that light is required for the maintenance, but not creation, of long-term memories.

https://www.sciencedaily.com/releases/2020/01/200113131644.htm

Lifestyle choices could slow familial frontotemporal dementia

Patients can influence outcomes despite a genetic diagnosis, study suggests

January 8, 2020

Science Daily/University of California - San Francisco

A physically and mentally active lifestyle confers resilience to frontotemporal dementia (FTD), even in people whose genetic profile makes the eventual development of the disease virtually inevitable, according to new research by scientists at the UC San Francisco Memory and Aging Center.

The research aligns with long-standing findings that exercise and cognitive fitness are one of the best ways to prevent or slow Alzheimer's disease, but is the first study to show that the same types of behaviors can benefit people with FTD, which is caused by a distinct form of brain degeneration.

FTD is a neurodegenerative disease that can disrupt personality, decision-making, language, or movement abilities, and typically begins between the ages of 45 and 65. It is the most common form of dementia in people under 65 (accounting for 5 to 15 percent of dementia cases overall) and typically results in rapid cognitive and physical decline and death in less than 10 years. There are currently no drugs to treat FTD, though numerous clinical trials for the disease are underway at UCSF Memory and Aging Center and elsewhere.

"This is devastating disease without good medical treatments, but our results suggest that even people with a genetic predisposition for FTD can still take actions to increase their chances of living a long and productive life. Their fate may not be set in stone," said Kaitlin Casaletto, PhD, assistant professor of neurology at the UCSF Memory and Aging Center and corresponding author of the new study, published January 8, 2020 in Alzheimer's and Dementia.

'If This Were a Drug, We Would Be Giving it to All Our Patients'

About 40 percent of people with FTD have a family history of the disease, and scientists have identified specific dominant genetic mutations that drive the development of the disease in roughly half of these cases. But even in these individuals, the disease can have very different courses and severity.

"There's incredible variability in FTD, even among people with the same genetic mutations driving their disease. Some people are just more resilient than others for reasons we still don't understand," said, Casaletto, a member of the UCSF Weill Institute for Neurosciences. "Our hypothesis was that the activities people engage in each day of their lives may contribute to the very different trajectories we see in clinic, including when the disease develops and how it progresses."

To test this hypothesis, Casaletto and colleagues studied how lifestyle differences affected FTD progression in 105 people with dominant, disease-causing genetic mutations who were mostly asymptomatic or had experienced only mild, early-stage symptoms. The research participants were drawn from two large multisite studies, called ARTFL and LEFFTDS (recently combined into a study known as ALLFTD), led by co-authors Adam Boxer, MD, PhD, and Howie Rosen, MD, also of the UCSF Memory and Aging Center.

As part of these larger studies, all participants underwent initial MRI scans to measure the extent of brain degeneration caused by the disease, completed tests of thinking and memory, and reported on their current levels of cognitive and physical activity in their daily lives (e.g., reading, spending time with friends, jogging). At the same time, their family members completed regular gold-standard assessments of how well the study participants were functioning in their lives -- managing finances, medications, bathing themselves, and so on. All of these measures were repeated at annual follow-up visits to track the long-term progression of participants' disease.

Even after only two to three visits (one to two years into the ongoing study), Casaletto and her team have already begun to see significant differences in the speed and severity of FTD between the most and least mentally and physically active individuals in the study, with mentally and physically active lifestyles showing similar effects across participants.

Specifically, the researchers found that functional decline, as assessed by participants' family members, was 55 percent slower in the most active 25 percent of participants compared to the least active five percent. "This was a remarkable effect to see so early on," Casaletto said. "If this were a drug, we would be giving it to all of our patients."

The researchers found that participants' lifestyles did not significantly alter the inexorable degeneration of brain tissue associated with FTD, as measured by follow-up MRI scans a year into the study. But even among participants whose brain scans revealed signs of atrophy, the most mentally and physically active participants continued to perform twice as well as the least active participants on cognitive tests. These results suggest that active lifestyles may slow FTD symptoms by providing some form of cognitive resilience to the consequences of brain degeneration.

Findings Could Illuminate Biology of Brain Resilience Across Dementias

The researchers anticipate seeing even larger differences in cognitive decline between more and less active groups as the merged ALLFTD study continues to follow these participants over time. "We've seen such significant effects in just the first year or two in people with very mild disease -- if these results hold, we may see that an active lifestyle sets individuals on a different trajectory for the coming years," Casaletto said.

The next step for the research is to include more detailed and objective assessments of participants' physical and mental activity -- including fitting them with wearable FitBit activity sensors -- to begin to estimate exactly how much activity is needed to promote cognitive resilience.

Casaletto cautions that the results, though exciting, so far only report a correlation: "It is possible that some participants have less active lifestyles because they have a more severe or aggressive form of FTD, which is already impacting their ability to be active. Clinical trials that manipulate cognitive and physical activity levels in people with FTD mutations are needed to prove that lifestyle changes can alter the course of the disease."

With this caveat in mind, Casaletto hopes the findings will not only encourage care teams and individuals with family histories of FTD to adopt lifestyle changes that could provide more productive years of life, but also that the ongoing study will lead to a better biological understanding of the drivers of resilience in people with FTD.

"We can see that lifestyle differences impact people's resilience to FTD despite very penetrant genetics, so now we can start to ask more fundamental questions, like how these behaviors actually affect the brain's biology to confer that resilience." Casaletto said. "Is that biological effect something we could replicate pharmacologically to help slow the progression of this terrible disease for everyone?"

https://www.sciencedaily.com/releases/2020/01/200108074801.htm

Alzheimer 'tau' protein far surpasses amyloid in predicting toll on brain tissue

Tau PET brain imaging could launch precision medicine era for Alzheimer's disease

January 1, 2020

Science Daily/University of California - San Francisco

The results support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.

Brain imaging of pathological tau-protein "tangles" reliably predicts the location of future brain atrophy in Alzheimer's patients a year or more in advance, according to a new study by scientists at the UC San Francisco Memory and Aging Center. In contrast, the location of amyloid "plaques," which have been the focus of Alzheimer's research and drug development for decades, was found to be of little utility in predicting how damage would unfold as the disease progressed.

The results, published January 1, 2020 in Science Translational Medicine, support researchers' growing recognition that tau drives brain degeneration in Alzheimer's disease more directly than amyloid protein, and at the same time demonstrates the potential of recently developed tau-based PET (positron emission tomography) brain imaging technology to accelerate Alzheimer's clinical trials and improve individualized patient care.

"The match between the spread of tau and what happened to the brain in the following year was really striking," said neurologist Gil Rabinovici, MD, the Edward Fein and Pearl Landrith Distinguished Professor in Memory and Aging and leader of the PET imaging program at the UCSF Memory and Aging Center. "Tau PET imaging predicted not only how much atrophy we would see, but also where it would happen. These predictions were much more powerful than anything we've been able to do with other imaging tools, and add to evidence that tau is a major driver of the disease."

Interest in Tau Growing as Amyloid-Based Therapies Stumble

Alzheimer's researchers have long debated the relative importance of amyloid plaques and tau tangles -- two kinds of misfolded protein clusters seen in postmortem studies of patients' brains, both first identified by Alois Alzheimer in the early 20th century. For decades, the "amyloid camp" has dominated, leading to multiple high-profile efforts to slow Alzheimer's with amyloid-targeting drugs, all with disappointing or mixed results.

Many researchers are now taking a second look at tau protein, once dismissed as simply a "tombstone" marking dying cells, and investigating whether tau may in fact be an important biological driver of the disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimer's patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients' symptoms (in language-related areas vs. memory-related regions, for example).

"No one doubts that amyloid plays a role in Alzheimer's disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease," explained Renaud La Joie, PhD, a postdoctoral researcher in Rabinovici's In Vivo Molecular Neuroimaging Lab, and lead author of the new study. "Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group's key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration."

Tau PET Scans Predict Locations of Future Brain Atrophy in Individual Patients

Despite early misgivings that tau might be impossible to measure in the living brain, scientists recently developed an injectable molecule called flortaucipir -- currently under review by the FDA -- which binds to misfolded tau in the brain and emits a mild radioactive signal that can be picked up by PET scans.

Rabinovici and collaborator William Jagust, MD, of UC Berkeley and Lawrence Berkeley National Laboratory, have been among the first to adopt tau PET imaging to study the distribution of tau tangles in the normally aging brain and in a smaller cross-sectional study of Alzheimer's patients. Their new study represents the first attempt to test whether tau levels in Alzheimer's patients can predict future brain degeneration.

La Joie recruited 32 participants with early clinical stage Alzheimer's disease through the UCSF Memory and Aging Center, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brain's structural integrity, both at the start of the study, and again in follow-up visits one to two years later.

The researchers found that overall tau levels in participants' brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration.

"Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer's disease," La Joie said.

Notably, PET scans revealed that younger study participants had higher overall levels of tau in their brains, as well as a stronger link between baseline tau and subsequent brain atrophy, compared to older participants. This suggests that other factors -- likely other abnormal proteins or vascular injuries -- may play a larger role in late-onset Alzheimer's, the researchers say.

Ability to Predict Brain Atrophy a 'Valuable Precision Medicine Tool'

The results add to hopes that tau-targeting drugs currently under study at the UCSF Memory and Aging Center and elsewhere may provide clinical benefits to patients by blocking this key driver of neurodegeneration in the disease. At the same time, the ability to use tau PET to predict later brain degeneration could enable more personalized dementia care and speed ongoing clinical trials, the authors say.

"One of the first things people want to know when they hear a diagnosis of Alzheimer's disease is simply what the future holds for themselves or their loved ones. Will it be a long fading of memory, or a quick decline into dementia? How long will the patient be able to live independently? Will they lose the ability to speak or get around on their own? These are questions we can't currently answer, except in the most general terms," Rabinovici said. "Now, for the first time, this tool could let us give patients a sense of what to expect by revealing the biological process underlying their disease."

Rabinovici and his team also anticipate that the ability to predict future brain atrophy based on tau PET imaging will allow Alzheimer's clinical trials to quickly assess whether an experimental treatment can alter the specific trajectory predicted for an individual patient, which is currently impossible due to the wide variability in how the disease progresses from individual to individual. Such insights could make it possible to adjust dosage or switch to a different experimental compound if the first treatment is not affecting tau levels or altering a patient's predicted trajectory of brain atrophy.

"Tau PET could be an extremely valuable precision medicine tool for future clinical trials," Rabinovici said. "The ability to sensitively track tau accumulation in living patients would for the first time let clinical researchers seek out treatments that can slow down or even prevent the specific pattern of brain atrophy predicted for each patient."

https://www.sciencedaily.com/releases/2020/01/200101144012.htm

Possible dementia vaccine closer after mice studies

Human trials tipped within two years

December 31, 2019

Science Daily/Flinders University

A vaccine to ward off dementia may proceed to clinical trials after successful animal testing. The research is looking to develop effective immunotherapy via a dual vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease. It is showing success in begenic mice models, supports progression to human trials in years to come.

A preventive treatment for dementia may proceed to clinical trials after successful animal testing.

The US-led research is looking to develop effective immunotherapy via a new vaccine to remove 'brain plaque' and tau protein aggregates linked to Alzheimer's disease.

Recent success in bigenic mice models supports progression to human trials in years to come, the researchers say.

A new paper in the journal Alzheimer's Research & Therapy paves the way for more work in 2020, with medical researchers at the Institute for Molecular Medicine and University of California, Irvine (UCI) working with a successful vaccine formulated on adjuvant developed by Flinders University Professor Nikolai Petrovsky in South Australia.

The latest research aims to come up with a new treatment to remove accumulated beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting about 5.7 million people in the US. Major challenges in AD include the lack of effective treatments, reliable biomarkers, or preventive strategies.

Professor of the Institute for Molecular Medicine Anahit Ghochikyan and colleagues, Associate Professors Hvat Davtyan and Mathew Blurton-Jones from UCI, and other co-authors tested the universal MultiTEP platform-based vaccines formulated in the adjuvant developed at Professor Petrovsky's Australian lab.

The possible new therapies were tested in bigenic mice with mix Aβ and tau pathologies.

"Taken together, these findings warrant further development of this dual vaccination strategy based on the MultiTEP technology for ultimate testing in human Alzheimer's disease," the lead authors Professor Ghochikyan and Blurton-Jones conclude.

Professor Petrovsky says the Advax adjuvant method is a pivotal system to help take the combination MultiTEP-based Aβ/tau vaccines therapy, as well as separate vaccines targeting these pathological molecules, to clinical trials -- perhaps within two years.

"Our approach is looking to cover all bases and get past previous roadblocks in finding a therapy to slow the accumulation of Aβ/tau molecules and delay AD progression in a the rising number of people around the world," says Professor Petrovsky, who will work in the US for the next three months.

Several promising drug candidates have failed in clinical trials so the search for new preventions or therapies continues.

A recent report on human monoclonal antibody, aducanumab, showed that high dose of this antibody reduced clinical decline in patients with early AD as measured by primary and secondary endpoints.

However, it is obvious that it could not be used as a preventive measure in healthy subjects due to the need for frequent (monthly) administration of high concentrations of immunotherapeutic.

Professor Ghochikyan says there is a pressing need to keep searching for new preventive vaccine to delay AD and slow down progression of this devastating disease.

The new combined vaccination approach could potentially be used to induce strong immune responses to both of the hallmark pathologies of AD in a broad population base of vaccinated subjects with high MHC (major histocompatibility complex) class II gene polymorphisms, the new paper concludes.

https://www.sciencedaily.com/releases/2019/12/191231111835.htm

Objective subtle cognitive difficulties predict amyloid accumulation and neurodegeneration

December 31, 2019

Science Daily/University of California - San Diego

Writing in the December 30, 2019 online issue of Neurology, researchers at University of California San Diego School of Medicine and Veterans Affairs San Diego Healthcare System report that accumulating amyloid -- an abnormal protein linked to neurodegenerative conditions such as Alzheimer's disease (AD) -- occurred faster among persons deemed to have "objectively-defined subtle cognitive difficulties" (Obj-SCD) than among persons considered to be "cognitively normal."

Classification of Obj-SCD, which has been previously shown to predict progression to mild cognitive impairment (MCI) and dementia, is determined using non-invasive but sensitive neuropsychological measures, including measures of how efficiently someone learns and retains new information or makes certain types of errors.

The new findings, say authors, suggest that Obj-SCD can be detected during the preclinical state of AD when amyloid plaques are accumulating in the brain, neurodegeneration is just starting, but symptoms of impairment on total scores on thinking and memory tests have not yet been recorded.

"The scientific community has long thought that amyloid drives the neurodegeneration and cognitive impairment associated with Alzheimer's disease," said senior author Mark W. Bondi, PhD, professor of psychiatry at UC San Diego School of Medicine and the VA San Diego Healthcare System. "These findings, in addition to other work in our lab, suggest that this is likely not the case for everyone and that sensitive neuropsychological measurement strategies capture subtle cognitive changes much earlier in the disease process than previously thought possible.

"This work, led by Dr. Kelsey Thomas, has important implications for research on treatment targets for AD, as it suggests that cognitive changes may be occurring before significant levels of amyloid have accumulated. It seems like we may need to focus on treatment targets of pathologies other than amyloid, such as tau, that are more highly associated with the thinking and memory difficulties that impact people's lives."

Study participants were enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), an on-going effort (launched in 2003) to test whether regular, repeated brain imaging, combined with other biological markers and clinical assessments, can measure the progression of MCI and early AD. Seven hundred and forty-seven persons were involved in this study: 305 deemed cognitively normal, 153 with Obj-SCD and 289 MCI. All underwent neuropsychological testing and both PET and MRI scans.

The research team found that amyloid accumulation was faster in persons classified with Obj-SCD than in the cognitively normal group. Those classified as Obj-SCD also experienced selective thinning of the entorhinal cortex, a region of the brain impacted very early in Alzheimer's disease and associated with memory, navigation and perception of time. Persons with MCI had more amyloid in their brain at the start of the study, but they did not have faster accumulation of amyloid compared to those with normal cognition. However, those with MCI had more widespread temporal lobe atrophy, including the hippocampus.

Broadly speaking, scientists believe that for most people, AD is likely caused by a combination of genetic, lifestyle and environmental factors. Increasing age is a primary, known risk factor. The amyloid hypothesis or amyloid cascade model posits that accumulating amyloid protein plaques in the brain kill neurons and gradually impair specific cognitive functions, such as memory, resulting in AD dementia. However, many scientists are now questioning the amyloid hypothesis given the large number of clinical trials in which drugs targeted and successfully cleared amyloid from the brain but did not impact the trajectory of cognitive decline.

The ability to identify those at risk for AD before significant impairment and before or during the phase of faster amyloid accumulation would be a clinical boon, said authors, providing both a way to monitor disease progression and a window of opportunity to apply potential preventive or treatment strategies.

Currently, both approaches are limited. Some risk factors for Alzheimer's can be minimized, such as not smoking, managing vascular risk factors such as hypertension or following a healthy diet with regular exercise. There are a handful of medications approved for treating symptoms of AD, but as yet, there is no cure.

"While the emergence of biomarkers of Alzheimer's disease has revolutionized research and our understanding of how the disease progresses, many of these biomarkers continue to be highly expensive, inaccessible for clinical use or not available to those with certain medical conditions," said first author Thomas, PhD, assistant professor of psychiatry at UC San Diego School of Medicine and research health scientist at the VA San Diego Healthcare System.

"A method of identifying individuals at risk for progression to AD using neuropsychological measures has the potential to improve early detection in those who may otherwise not be eligible for more expensive or invasive screening."

https://www.sciencedaily.com/releases/2019/12/191231111811.htm

Alzheimer's study shows promise in protecting brain from tau

Researchers discover impact of MSUT2 gene and binding protein, offering others a starting point for new therapeutics

December 18, 2019

Science Daily/University of Washington Health Sciences/UW Medicine

In the wake of recent disappointments over clinical trials targeting amyloid plaque build-up in Alzheimer's disease, researchers are focusing more attention on misfolded tau protein, another culprit in brain diseases that cause dementia.

New research published in Science Translational Medicine finds that targeting abnormal tau through the suppression of a gene called MSUT2 (mammalian suppressor of tauopathy 2) shows promise.

Tau, like amyloid protein, is another substance that builds up in Alzheimer's disease and damages brain cells.

However, clinical trials targeting tau have been far less numerous in part because tau-targeted drugs have been hard to find.

In this study, researchers concluded that suppressing MSUT2 might protect people from Alzheimer's disease as long as the RNA binding protein PolyA Binding Protein Nuclear 1 (PABPN1) is not depleted. MSUT2 and PABPNI normally work together closely to regulate the biology of tau in the brain.

"If you inhibit MSUT2 and don't affect PABN1, that protects against the effects of tau pathology," said senior author Brian Kraemer, a research associate professor of medicine, Division of Gerontology and Geriatric Medicine at the University of Washington School of Medicine. He is also a scientist at the Veterans Affairs Puget Sound Health Care System.

Kraemer said his team sees their role as the person kicking the ball down field to provide other researchers and drug companies an opportunity to move the ball towards the ultimate goal: A treatment or cure for Alzheimer's disease.

"Pharmaceutical companies have heavily invested in going after amyloid but so far these efforts haven't moved the needle on dementia treatments," he said. "I think the field needs to think about targeting amyloid and tau together because both amyloid and tau act together to kill neurons in Alzheimer's disease."

Senior author Jeanna Wheeler, a research scientist at the Seattle Institute for Biomedical and Clinical Research and the VA, said what's novel about the study is the discovery of the role of the MSUT2 gene.

"We discovered MSUT2 originally in a completely unbiased way by looking for anything that could make worms resistant to pathological tau protein. Now we have shown that this gene can also affect tau toxicity in mice, and also that there are differences in MSUT2 in human Alzheimer's patients," she said. "If we can use MSUT2 in the future as a drug target, this would be a completely novel approach for treating Alzheimer's and other related disorders."

The study also brings more attention to the role of tau pathology in Alzheimer's disease.

The healthy human brain contains tens of billions of specialized cells or neurons that process and transmit information. By disrupting communication among these cells, Alzheimer's disease results in loss of neuron function and cell death.

Previous studies have shown that abnormal tau burden correlates strongly with cognitive decline in Alzheimer's disease patients, but amyloid does not. Some dementia disorders, such as frontotemporal lobar degeneration, may have only abnormal tau with no amyloid deposits.

"If you could protect the brain from tau alone, you may provide substantial benefit for people with Alzheimer's disease," Kraemer said. "Likewise, targeting tau in tangle-only Alzheimer's disease-related dementia disorders, like frontotemporal lobar degeneration, will almost certainly be beneficial for patients."

This study follows previous work by these researchers that showed very similar results using the worm C. elegans. Worms go from egg to adult in three days so it was easier to do experiments on the biology of aging rapidly. Although worms don't have complex cognitive functions, their movement is affected by tau buildup. Researchers found that they could cure the worm by knocking out the worm sut-2 gene.

The more recent study applied the experiment to mice, whose evolutionary distance to humans is much smaller than the distance between worms and humans.

The researchers knocked out the MSUT2 gene in mice, thereby, preventing the formation of the tau tangles that kill off brain cells. This lessened learning and memory problems as well.

While examining autopsy brain samples from Alzheimer's patients, the researchers found that cases with more severe disease lacked both MSUT2 protein, and its partner protein, PABPN1. This finding suggests that neurons that lose the MSUT2 -PABPN1 protein partnership may simply die during a patient's life.

Moreover, mice lacking MSUT2 but possessing a normal complement of PABPN1 were strongly protected against abnormal tau and the resulting brain degeneration. Therefore, the researchers concluded that the key to helping people with abnormal tau buildup is blocking MSUT2 while preserving PABPN1 activity.

https://www.sciencedaily.com/releases/2019/12/191218153505.htm

Are herpes virus infections linked to Alzheimer's disease?

December 18, 2019

Science Daily/Baylor College of Medicine

Researchers at Baylor College of Medicine report today in the journal Neuron evidence that refutes the link between increased levels of herpes virus and Alzheimer's disease. In addition, the researchers provide a new statistical and computational framework for the analysis of large-scale sequencing data.

About 50 million people worldwide are affected by Alzheimer's disease, a type of progressive dementia that results in the loss of memory, cognitive abilities and verbal skills, and the numbers are growing rapidly. Currently available medications temporarily ease the symptoms or slow the rate of decline, which maximizes the time patients can live and function independently. However, there are no treatments to halt progression of Alzheimer's disease.

"Like all types of dementia, Alzheimer's disease is characterized by massive death of brain cells, the neurons. Identifying the reason why neurons begin and continue to die in the brains of Alzheimer's disease patients is an active area of research," said corresponding author Dr. Zhandong Liu, associate professor of pediatrics at Baylor and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

One theory that has gained traction in the past year is that certain microbial infections, such as those caused by viruses, can trigger Alzheimer's disease. A 2018 study reported increased levels of human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) in the postmortem brain tissues of more than 1,000 patients with Alzheimer's disease when compared to the brain tissues of healthy-aging subjects or those suffering from a different neurodegenerative condition.

Presence of elevated levels of genetic material of herpes viruses indicated active infections, which were linked to Alzheimer's disease. In less than a year, this study generated a flurry of excitement and led to the initiation of several studies to better understand the link between viral infections and Alzheimer's disease.

Surprisingly, when co-author Dr. Hyun-Hwan Jeong, a postdoctoral fellow in Dr. Liu's group and others, reanalyzed the data sets from the 2018 study using the identical statistical methods with rigorous filtering, as well as four commonly used statistical tools, they were unable to produce the same results.

The team was motivated to reanalyze the data from the previous study because they observed that while the p-values (a statistical parameter that predicts the probability of obtaining the observed results of a test, assuming that other conditions are correct) were highly significant, they were being ascribed to data in which the differences were not visually appreciable.

Moreover, the p-values did not fit with simple logistic regression -- a statistical analysis that predicts the outcome of the data as one of two defined states. In fact, after several types of rigorous statistical tests, they found no link between the abundance of herpes viral DNA or RNA and likelihood of Alzheimer's disease in this cohort.

"As high-throughput 'omics' technologies, which include those for genomics, proteomics, metabolomics and others, become affordable and easily available, there is a rising trend toward 'big data' in basic biomedical research. In these situations, given the massive amounts of data that have to be mined and extracted in a short time, researchers may be tempted to rely solely on p-values to interpret results and arrive at conclusions," Liu said.

"Our study highlights one of the potential pitfalls of over-reliance on p-values. While p-values are a very valuable statistical parameter, they cannot be used as a stand-alone measure of statistical correlation -- data sets from high-throughput procedures still need to be carefully plotted to visualize the spread of the data," Jeong said. "Data sets also have to be used in conjunction with accurately calculated p-values to make gene-disease associations that are statistically correct and biologically meaningful."

"Our goal in pursuing and publishing this study was to generate tools and guidelines for big data analysis, so the scientific community can identify treatment strategies that will likely benefit patients," Liu said.

https://www.sciencedaily.com/releases/2019/12/191218153350.htm

Changes in the immune system explain why belly fat is bad for thinking

December 17, 2019

Science Daily/Iowa State University

Researchers have found for the first time that less muscle and more body fat may affect how flexible our thinking gets as we become older, and changes in parts of the immune system could be responsible.

These findings could lead to new treatments that help maintain mental flexibility in aging adults with obesity, sedentary lifestyles, or muscle loss that naturally happens with aging.

The study, led by Auriel Willette, assistant professor of food science and human nutrition, and Brandon Klinedinst, a PhD student in neuroscience, looked at data from more than 4,000 middle-aged to older UK Biobank participants, both men and women. The researchers examined direct measurements of lean muscle mass, abdominal fat, and subcutaneous fat, and how they were related to changes in fluid intelligence over six years.

Willette and Klinedinst discovered people mostly in their 40s and 50s who had higher amounts of fat in their mid-section had worse fluid intelligence as they got older. Greater muscle mass, by contrast, appeared to be a protective factor. These relationships stayed the same even after taking into account chronological age, level of education, and socioeconomic status.

"Chronological age doesn't seem to be a factor in fluid intelligence decreasing over time," Willette said. "It appears to be biological age, which here is the amount of fat and muscle."

Generally, people begin to gain fat and lose lean muscle once they hit middle age, a trend that continues as they get older. To overcome this, implementing exercise routines to maintain lean muscle becomes more important. Klinedinst said exercising, especially resistance training, is essential for middle-aged women, who naturally tend to have less muscle mass than men.

The study also looked at whether or not changes in immune system activity could explain links between fat or muscle and fluid intelligence. Previous studies have shown that people with a higher body mass index (BMI) have more immune system activity in their blood, which activates the immune system in the brain and causes problems with cognition. BMI only takes into account total body mass, so it has not been clear whether fat, muscle, or both jump-start the immune system.

In this study, in women, the entire link between more abdominal fat and worse fluid intelligence was explained by changes in two types of white blood cells: lymphocytes and eosinophils. In men, a completely different type of white blood cell, basophils, explained roughly half of the fat and fluid intelligence link. While muscle mass was protective, the immune system did not seem to play a role.

While the study found correlations between body fat and decreased fluid intelligence, it is unknown at this time if it could increase the risk of Alzheimer's disease.

"Further studies would be needed to see if people with less muscle mass and more fat mass are more likely to develop Alzheimer's disease, and what the role of the immune system is," Klinedinst said.

Starting a New Year's resolution now to work out more and eat healthier may be a good idea, not only for your overall health, but to maintain healthy brain function.

"If you eat alright and do at least brisk walking some of the time, it might help you with mentally staying quick on your feet," Willette said.

https://www.sciencedaily.com/releases/2019/12/191217141531.htm

How a protein in your brain could protect against Alzheimer's disease

New research sets the stage for new therapeutic strategies for Alzheimer's disease

December 13, 2019

University of Alberta

Research shows that white blood cells in the human brain are regulated by a protein called CD33--a finding with important implications in the fight against Alzheimer's disease, according to a new study.

 "Immune cells in the brain, called microglia, play a critical role in Alzheimer's disease," explained Matthew Macauley, assistant professor in theDepartment of Chemistry and co-author on the paper. "They can be harmful or protective. Swaying microglia from a harmful to protective state could be the key to treating the disease."

Scientists have identified the CD33 protein as a factor that may decrease a person's likelihood of Alzheimer's disease. Less than 10 percent of the population have a version of CD33 that makes them less likely to get Alzheimer's disease. "The fact that CD33 is found on microglia suggests that immune cells can protect the brain from Alzheimer's disease under the right circumstances," said Abhishek Bhattacherjee, first author and postdoctoral fellow in the Macauley lab.

Now, Macauley's research shows that the most common type of CD33 protein plays a crucial role in modulating the function of microglia.

"These findings set the stage for future testing of a causal relationship between CD33 and Alzheimer's Disease, as well as testing therapeutic strategies to sway microglia from harmful to protecting against the disease -- by targeting CD33," said Macauley. "Microglia have the potential to 'clean up' the neurodegenerative plaques, through a process called phagocytosis -- so a therapy to harness this ability to slow down or reverse Alzheimer's disease can be envisioned."

Macauley is an investigator with GlycoNet, a Canada-wide network of researchers based at the University of Alberta that is working to further our understanding of biological roles for sugars. GlycoNet provided key funding to get this project off the ground in the Macauley lab and continues to support the ongoing applications of the project.

According to the Alzheimer's Association, 747,000 Canadians are currently living with Alzheimer's or another form of dementia. The disease affects more than 44 million people around the world.

https://www.sciencedaily.com/releases/2019/12/191213124921.htm

Dementia study reveals how proteins interact to stop brain signals

December 10, 2019

University of Edinburgh

Fresh insights into damaging proteins that build up in the brains of people with Alzheimer's disease could aid the quest for treatments.

A study in mice reveals how the two proteins work together to disrupt communication between brain cells.

Scientists observed how proteins -- called amyloid beta and tau -- team up to hamper key genes responsible for brain messaging. By changing how genes are expressed in the brain, the proteins can affect its normal function.

These changes in brain function were completely reversed when genetic tools were used to reduce the presence of tau, researchers at the University of Edinburgh found.

The study focused on the connection points between brain cells -- known as synapses -- that allow chemical and electrical messages to flow and are vital to healthy brain function.

Stopping the damage that the two proteins cause to synapses could help scientists prevent or reverse dementia symptoms, the researchers say.

In both the mouse model and in brain tissue from people with Alzheimer's disease, the team found clumps of amyloid beta and tau proteins in synapses.

When both amyloid beta and tau were present in the brain, genes that control the function of synapses were less active. And some of the genes that control the immune system in the brain were more active.

Related to increased immune system activity, the scientists observed immune cells called microglia containing synapses in the brains of mice. This adds to findings from recent studies suggesting that these immune cells consume synapses during Alzheimer's disease.

Alzheimer's disease is the most common form of dementia, affecting some 850,000 people in the UK -- a figure predicted to rise to more than one million by 2025. It can cause severe memory loss and there is currently no cure.

Lead researcher, Professor Tara-Spires Jones of the UK Dementia Research Institute at the University of Edinburgh, said: "More work is needed to take what we've learned in this study and find therapeutics -- but this is a step in the right direction, giving us new targets to work towards."

The study is published in the journal Cell Reports. It was funded by the European Research Council, and the UK Dementia Research Institute which is funded by the UK Medical Research Council, Alzheimer' Society and Alzheimer's Research UK.

https://www.sciencedaily.com/releases/2019/12/191210111726.htm

Scientists eager to explain brain rhythm boost's broad impact in Alzheimer's models

December 11, 2019

Science Daily/Picower Institute at MIT

Neuroscientists lay out the the few knowns and many unknowns that must be understood to determine why sensory stimuluation of 40Hz brain rhythms have broad effects, particularly in Alzheimer's models.

The sweeping extent to which increasing 40Hz "gamma" rhythm power in the brain can affect the pathology and symptoms of Alzheimer's disease in mouse models has been surprising, even to the MIT neuroscientists who've pioneered the idea. So surprising, in fact, they can't yet explain why it happens.

In three papers, including two this year in Cell and Neuron, they've demonstrated that exposing mice to light flickering or sound buzzing at 40Hz, a method dubbed "GENUS" for Gamma Entrainment Using Sensory stimuli, strengthens the rhythm across the brain and changes the gene expression and activity of multiple brain cell types. Pathological amyloid and tau protein buildups decline, neurons and their circuit connections are protected from degeneration and learning and memory endure significantly better than in disease model mice who do not receive GENUS.

In a new review article in Trends in Neurosciences two researchers leading those efforts lay out the few knowns and many unknowns that must be understood to determine how the widespread effects take place. It's a challenge they relish because the answers could both break new scientific ground and help them improve how GENUS could become a therapeutic or preventative approach for people.

"While we know it affects pathology in mice, we want to understand how because that will help us understand and refine potential treatment," said lead author Chinnakkaruppan Adaikkan, a postdoc in the lab of senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute for Learning and Memory.

Adaikkan has been interested in understanding how neural activity produces brain rhythms since his doctoral research. At MIT, he is channeling that passion into understanding how sensory stimulation can entrain oscillations.

"That's what drives me to come to the lab every day to study these mechanisms," Adaikkan said. "When we got the data from the first mouse where we recorded from the visual cortex, the hippocampus and the prefrontal cortex we were surprised to see that visual stimulation entrains in these brain regions. That was very exciting but we have a very long way to go to understand how this happens."

The new paper raises that question and many others for the field. What cells underlie the brain's response to GENUS? How do gamma rhythms engage non-neuronal cells such as astrocytes and microglia? How does it propagate beyond the brain regions responsible for perception? How extensively can enhancing gamma affect cognition? Does long-term stimulation affect brain circuit connections and how they change?

Cell roles

Studies of how groups of neurons engage in coherent oscillations of electrical activity have yielded two models to explain gamma rhythms. Both involve an interplay between excitatory and inhibitory neurons but differ on which type leads the interaction, Adaikkan and Tsai wrote. In his work, Adaikkan is attempting to dissect the roles of specific neuron types in GENUS and how closely those patterns mirror other sources of gamma, such as that invoked by cognitive tasks.

GENUS affects more than neurons. Tsai's lab has found that microglia change their gene expression, their physical form, their protein-consuming behavior and their inflammatory response depending on the Alzheimer's model involved. Work from another group showed that blocking vesicle release in astrocytes can hinder gamma power in mice and Tsai's group found that auditory GENUS recruits an increase reactive astrocytes, which are more inclined to consume pathological proteins.

The new paper offers three hypotheses about how such "glial" cells are involved: They might contribute directly to gamma entrainment by regulating the flow of ions that carry electrical charge; even if they don't contribute to rhythms, their ionic sensitivity may still make them responsive to gamma changes; they might instead be affected by changes in levels of neurotransmitters as a result of gamma.

Moreover, different glia may also become involved because of their proximity to electrical couplings between neurons called synapses, or because of how their activity is otherwise governed by neural activity.

The broader brain

That GENUS extends to the hippocampus, which is key for memory, and the prefrontal cortex, which is key for cognition, is likely a factor in how it preserves brain function. But again there are competing models for how increased gamma could facilitate multi-regional communication. In one, the authors write, coherence at the same frequency optimizes communication, while in the other model, one region's gamma activity directly drives activity in regions downstream. New experiments that directly manipulate inter-regional circuits, they argue, could help resolve which model better explains gamma entrainment's effects.

Finally, the effects of GENUS on brain function and behavior also aren't fully explained. The Tsai lab's has shown significant effects on spatial memory and some effects on other forms of memory, depending on the stimulation method. Other studies have shown that stimulating brain rhythms by other means, such as via genetic or optogenetic manipulations in mice, or via transcranial stimulation in humans, can also improve functions such as working memory. Adaikkan is interested in closing a gap between those studies and the Tsai lab's work: Most studies measure cognitive performance during stimulation, while the Tsai lab has done so after the conclusion of repeated stimulation. He said he'd like to also test how mice perform while GENUS is actively underway.

"Our lab is excited to tackle these many hypotheses and to see how the field tackles many more," Tsai said. "GENUS has created many intriguing new questions for neuroscience."

https://www.sciencedaily.com/releases/2019/12/191211115624.htm

How playing the drums changes the brain

Many years of playing the instrument leave clear traces

December 9, 2019

Science Daily/Ruhr-University Bochum

People who play drums regularly for years differ from unmusical people in their brain structure and function. The results of a study by researchers from Bochum suggest that they have fewer, but thicker fibres in the main connecting tract between the two halves of the brain. In addition, their motor brain areas are organised more efficiently. This is the conclusion drawn by a research team headed by Dr. Lara Schlaffke from the Bergmannsheil university clinic in Bochum and Associate Professor Dr. Sebastian Ocklenburg from the biopsychology research unit at Ruhr-Universität Bochum following a study with magnetic resonance imaging (MRI). The results have been published in the journal Brain and Behavior, online on 4 December 2019.

Drummers were never previously studied

"It has long been understood that playing a musical instrument can change the brain via neuroplastic processes," says Sarah Friedrich, who wrote her bachelor's thesis on this project. "But no one had previously looked specifically into drummers," she adds.

The researchers from Bochum were interested in this group because their motor coordination far surpasses that of untrained people. "Most people can only perform fine motor tasks with one hand and have problems playing different rhythms with both hands at the same time," explains Lara Schlaffke. "Drummers can do things that are impossible for untrained people."

Drumming first, then brain scans

The team intended to gain new insights into the organisation of complex motor processes in the brain by identifying the changes in the brain caused by this training. The researchers tested 20 professional drummers who have played their instrument for an average of 17 years and currently practice for more than ten hours per week. They examined them using various MRI imaging techniques that provide insights into the structure and function of the brain. They then compared the data with measurements of 24 unmusical control subjects. In the first step, both groups had to play drums to test their abilities and were then examined in the MRI scanner.

More efficient motor processing

Drummers presented clear differences in the front part of the corpus callosum, a brain structure that connects the two hemispheres and whose front part is responsible for motor planning. The data indicated that the drummers had fewer but thicker fibres in this important connecting tract between the brain hemispheres. This allows musicians to exchange information between the hemispheres more quickly than the controls. The structure of the corpus callosum also predicted the performance in the drum test: the higher the measure of the thickness of the fibres in the corpus callosum, the better the drumming performance.

Moreover, the brain of drummers was less active in motor tasks than that of control subjects. This phenomenon is referred to as sparse sampling: a more efficient brain organisation in the areas leads to less activation in professionals.

Older participants wanted for new study

"We would like to thank our highly motivated participants who took part in the study," says Lara Schlaffke. "It was great fun working with you."

https://www.sciencedaily.com/releases/2019/12/191209110513.htm

Improving blood vessel health in brain may help combat Alzheimer's

December 5, 2019

Science Daily/Massachusetts General Hospital

Researchers have found that very slow spontaneous blood vessel pulsations drive the clearance of substances from the brain, indicating that targeting and improving this process may help to prevent or treat amyloid-beta accumulation.

In patients with Alzheimer's disease, amyloid-beta protein fragments accumulate in the tissue and blood vessels of the brain, likely due to a faulty clearance mechanism. In experiments conducted in mice, investigators at Massachusetts General Hospital (MGH) have found that very slow spontaneous vessel pulsations -- also known as 'vasomotion' -- drive the clearance of substances from the brain, indicating that targeting and improving this process may help to prevent or treat amyloid-beta accumulation.

In their study published in Neuron, the researchers injected a fluorescently labeled carbohydrate called dextran into the brains of awake mice, and they conducted imaging tests to follow its clearance. Their experiments revealed that vasomotion was critical for clearing dextran from the brain and stimulating an increase of the amplitude of these vessel pulsations could increase clearance. Also, in mice with cerebral amyloid angiopathy, a condition that causes amyloid-beta to build up in the walls of the brain's blood vessels, vessel pulsations were hindered and clearance rates were reduced.

"We were able to show for the first time that large dilations and contractions of vessels that happen spontaneously at an ultra-low frequency are a major driving force to clear waste products from the brain," said lead author Susanne van Veluw, PhD, an investigator in the department of Neurology at MGH. "Our findings highlight the importance of the vasculature in the pathophysiology of Alzheimer's disease. If we direct therapeutic strategies towards promoting healthy vasculature and therefore improve clearance of amyloid-beta from the brain, we may be able to prevent or delay the onset of Alzheimer's disease in the future."

https://www.sciencedaily.com/releases/2019/12/191205073031.htm

Inflammatory processes drive progression of Alzheimer's and other brain diseases

New insights into disease mechanisms, report in Nature

November 20, 2019

Science Daily/DZNE - German Center for Neurodegenerative Diseases

Inflammation drives the progression of neurodegenerative brain diseases and plays a major role in the accumulation of tau proteins within neurons. An international research team led by the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn comes to this conclusion in the journal Nature. The findings are based on the analyses of human brain tissue and further lab studies. In the particular case of Alzheimer's the results reveal a hitherto unknown connection between Abeta and tau pathology. Furthermore, the results indicate that inflammatory processes represent a potential target for future therapies.

Tau proteins usually stabilize a neuron's skeleton. However, in Alzheimer's disease, frontotemporal dementia (FTD), and other "tauopathies" these proteins are chemically altered, they detach from the cytoskeleton and stick together. As a consequence, the cell's mechanical stability is compromised to such an extent that it dies off. In essence, "tau pathology" gives neurons the deathblow. The current study led by Prof. Michael Heneka, director of the Department of Neurodegenerative Diseases and Gerontopsychiatry at the University of Bonn and a senior researcher at the DZNE, provides new insights into why tau proteins are transformed. As it turns out, inflammatory processes triggered by the brain's immune system are a driving force.

A Molecular Switch

A particular protein complex, the "NLRP3 inflammasome," plays a central role for these processes, the researchers report in Nature. Heneka and colleagues already studied this macromolecule, which is located inside the brain's immune cells, in previous studies. It is a molecular switch that can trigger the release of inflammatory substances. For the current study, the researchers examined tissue samples from the brains of deceased FTD patients, cultured brain cells, and mice that exhibited hallmarks of Alzheimer's and FTD.

"Our results indicate that the inflammasome and the inflammatory reactions it triggers, play an important role in the emergence of tau pathology," Heneka said. In particular, the researchers discovered that the inflammasome influences enzymes that induce a "hyperphosphorylation" of tau proteins. This chemical change ultimately causes them to separate from the scaffold of neurons and clump together. "It appears that inflammatory processes mediated by the inflammasome are of central importance for most, if not all, neurodegenerative diseases with tau pathology."

A Link between Abeta and Tau

This especially applies to Alzheimer's disease. Here another molecule comes into play: "amyloid beta" (Abeta). In Alzheimer's, this protein also accumulates in the brain. In contrast to tau proteins, this does not happen within the neurons but between them. In addition, deposition of Abeta starts in early phases of the disease, while aggregation of tau proteins occurs later.

In previous studies, Heneka and colleagues were able to show that the inflammasome can promote the aggregation of Abeta. Here is where the connection to the recent findings comes in. "Our results support the amyloid cascade hypothesis for the development of Alzheimer's. According to this hypothesis, deposits of Abeta ultimately lead to the development of tau pathology and thus to cell death," said Heneka. "Our current study shows that the inflammasome is the decisive and hitherto missing link in this chain of events, because it bridges the development from Abeta pathology to tau pathology. It passes the baton, so to speak." Thus, deposits of Abeta activate the inflammasome. As a result, formation of further deposits of Abeta is promoted. On the other hand, chemical changes occur to the tau proteins resulting into their aggregation.

A Possible Starting Point for Therapies

"Inflammatory processes promote the development of Abeta pathology, and as we have now been able to show, of tau pathology as well. Thus, the inflammasome plays a key role in Alzheimer's and other brain diseases," said Heneka, who is involved in the Bonn-based "ImmunoSensation" cluster of excellence and who also teaches at the University of Massachusetts Medical School. With these findings, the neuroscientist sees opportunities for new treatment methods. "The idea of influencing tau pathology is obvious. Future drugs could tackle exactly this aspect by modulating the immune response. With the development of tau pathology, mental abilities decline more and more. Therefore, if tau pathology could be contained, this would be an important step towards a better therapy."

https://www.sciencedaily.com/releases/2019/11/191120131318.htm

Are we 'brainwashed' during sleep?

Cerebrospinal fluid washes in and out of brain during sleep

October 31, 2019

Science Daily/Boston University

New research from Boston University suggests that tonight while you sleep, something amazing will happen within your brain. Your neurons will go quiet. A few seconds later, blood will flow out of your head. Then, a watery liquid called cerebrospinal fluid (CSF) will flow in, washing through your brain in rhythmic, pulsing waves.

The study, published on October 31 in Science, is the first to illustrate that the brain's CSF pulses during sleep, and that these motions are closely tied with brain wave activity and blood flow.

"We've known for a while that there are these electrical waves of activity in the neurons," says study coauthor Laura Lewis, a BU College of Engineering assistant professor of biomedical engineering and a Center for Systems Neuroscience faculty member. "But before now, we didn't realize that there are actually waves in the CSF, too."

This research may also be the first-ever study to take images of CSF during sleep. And Lewis hopes that it will one day lead to insights about a variety of neurological and psychological disorders that are frequently associated with disrupted sleep patterns, including autism and Alzheimer's disease.

The coupling of brain waves with the flow of blood and CSF could provide insights about normal age-related impairments as well. Earlier studies have suggested that CSF flow and slow-wave activity both help flush toxic, memory-impairing proteins from the brain. As people age, their brains often generate fewer slow waves. In turn, this could affect the blood flow in the brain and reduce the pulsing of CSF during sleep, leading to a buildup of toxic proteins and a decline in memory abilities. Although researchers have tended to evaluate these processes separately, it now appears that they are very closely linked.

To further explore how aging might affect sleep's flow of blood and CSF in the brain, Lewis and her team plan to recruit older adults for their next study, as the 13 subjects in the current study were all between the ages of 23 and 33. Lewis says they also hope to come up with a more sleep-conducive method of imaging CSF. Wearing EEG caps to measure their brain waves, these initial 13 subjects were tasked with dozing off inside an extremely noisy MRI machine, which, as anyone who has had an MRI can imagine, is no easy feat.

"We have so many people who are really excited to participate because they want to get paid to sleep," Lewis says with a laugh. "But it turns out that their job is actually -- secretly -- almost the hardest part of our study. We have all this fancy equipment and complicated technologies, and often a big problem is that people can't fall asleep because they're in a really loud metal tube, and it's just a weird environment."

But for now, she is glad to have the opportunity to take images of CSF at all. One of the most fascinating yields of this research, Lewis says, is that they can tell if a person is sleeping simply by examining a little bit of CSF on a brain scan.

"It's such a dramatic effect," she says. "[CSF pulsing during sleep] was something we didn't know happened at all, and now we can just glance at one brain region and immediately have a readout of the brain state someone's in."

As their research continues to move forward, Lewis' team has another puzzle they want to solve: How exactly are our brain waves, blood flow, and CSF coordinating so perfectly with one another? "We do see that the neural change always seems to happen first, and then it's followed by a flow of blood out of the head, and then a wave of CSF into the head," says Lewis.

One explanation may be that when the neurons shut off, they don't require as much oxygen, so blood leaves the area. As the blood leaves, pressure in the brain drops, and CSF quickly flows in to maintain pressure at a safe level.

"But that's just one possibility," Lewis says. "What are the causal links? Is one of these processes causing the others? Or is there some hidden force that is driving all of them?"

https://www.sciencedaily.com/releases/2019/10/191031174650.htm

High-intensity exercise improves memory in seniors

October 31, 2019

Science Daily/McMaster University

Researchers at McMaster University who examine the impact of exercise on the brain have found that high-intensity workouts improve memory in older adults.

The study, published in the journal Applied Physiology, Nutrition and Metabolism, has widespread implications for treating dementia, a catastrophic disease that affects approximately half a million Canadians and is expected to rise dramatically over the next decade.

Researchers suggest that intensity is critical. Seniors who exercised using short, bursts of activity saw an improvement of up to 30% in memory performance while participants who worked out moderately saw no improvement, on average.

"There is urgent need for interventions that reduce dementia risk in healthy older adults. Only recently have we begun to appreciate the role that lifestyle plays, and the greatest modifying risk factor of all is physical activity," says Jennifer Heisz, an associate professor in the Department of Kinesiology at McMaster University and lead author of the study.

"This work will help to inform the public on exercise prescriptions for brain health so they know exactly what types of exercises boost memory and keep dementia at bay," she says.

For the study, researchers recruited dozens of sedentary but otherwise healthy older adults between the ages of 60 and 88 who were monitored over a 12-week period and participated in three sessions per week. Some performed high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) while a separate control group engaged in stretching only.

The HIIT protocol included four sets of high-intensity exercise on a treadmill for four minutes, followed by a recovery period. The MICT protocol included one set of moderate-intensity aerobic exercise for nearly 50 minutes.

To capture exercise-related improvements in memory, researchers used a specific test that taps into the function of the newborn neurons generated by exercise which are more active than mature ones and are ideal for forming new connections and creating new memories.

They found older adults in the HIIT group had a substantial increase in high-interference memory compared to the MICT or control groups. This form of memory allows us to distinguish one car from another of the same make or model, for example.

Researchers also found that improvements in fitness levels directly correlated with improvement in memory performance.

"It's never too late to get the brain health benefits of being physically active, but if you are starting late and want to see results fast, our research suggests you may need to increase the intensity of your exercise," says Heisz.

She cautions that it is important to tailor exercise to current fitness levels, but adding intensity can be as simple as adding hills to a daily walk or increasing pace between street lamps.

"Exercise is a promising intervention for delaying the onset of dementia. However, guidelines for effective prevention do not exist. Our hope is this research will help form those guidelines."

https://www.sciencedaily.com/releases/2019/10/191031112522.htm

How will your thinking and memory change with age?

October 30, 2019

Science Daily/American Academy of Neurology

How well eight-year-olds score on a test of thinking skills may be a predictor of how they will perform on tests of thinking and memory skills when they are 70 years old, according to a study published in the October 30, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study also found that education level and socioeconomic status were also predictors of thinking and memory performance. Socioeconomic status was determined by people's occupation at age 53.

"Finding these predictors is important because if we can understand what influences an individual's cognitive performance in later life, we can determine which aspects might be modifiable by education or lifestyle changes like exercise, diet or sleep, which may in turn slow the development of cognitive decline," said study author Jonathan M. Schott, MD, FRCP, of University College London in the United Kingdom and a member of the American Academy of Neurology.

The study involved 502 people all born during the same week in 1946 in Great Britain who took cognitive tests when they were eight years old. Between the ages of 69 and 71, participants took thinking and memory tests again. One test, similar to a test they completed as children, involved looking at various arrangements of geometric shapes and identifying the missing piece from five options. Other tests evaluated skills like memory, attention, orientation and language.

Participants had positron emission tomography (PET) scans to see if they had amyloid-beta plaques in the brain associated with Alzheimer's disease. They also had detailed brain magnetic resonance imaging scans (MRI).

Researchers found that childhood thinking skills were associated with scores on the cognitive tests taken more than 60 years later. For example, someone whose cognitive performance was in the top 25 percent as a child, was likely to remain in the top 25 percent at age 70. Even accounting for differences in childhood test scores, there was an additional effect of education. For example, participants who completed a college degree scored around 16 percent higher than participants who left school before the age of 16. Having a higher socioeconomic status also predicted slightly better cognitive performance at age 70, but the effect was very small. For example, those who had worked in professional jobs tended to recall an average of 12 details from a short story, compared to 11 details for those who had worked in manual jobs. Women performed better than men in test of memory and thinking speed.

In addition, researchers found that participants with amyloid-beta plaques had lower scores on cognitive testing. For example, on the missing pieces test, they scored 8 percent lower on average. In other words, they got 23 out of 32 items correct on average -- 2 points lower than participants without amyloid-beta plaques. However the presence of these plaques was not associated with sex, childhood cognitive skills, education or socioeconomic status.

"Our study found that small differences in thinking and memory associated with amyloid plaques in the brain are detectible in older adults even at an age when those who are destined to develop dementia are still likely to be many years away from having symptoms," said Schott. "It also found that childhood cognitive skills, education and socioeconomic status all independently influence cognitive performance at age 70. Continued follow-up of these individuals, and future studies are needed to determine how to best use these findings to more accurately predict how a person's thinking and memory will change as they age."

A limitation of the study is that all participants were white, so the results may not represent the general population.

The study was supported by Alzheimer's Research UK, the Medical Research Council Dementia Platform UK and the Wolfson Foundation. Brain Research UK funded the genetic analyses. AVID Radiopharmaceuticals provided florbetapir amyloid tracer for the PET scans, but had no part in the design of the study.

https://www.sciencedaily.com/releases/2019/10/191030170554.htm

Living in a noisy area increases the risk of suffering a more serious stroke

The work analysed data from nearly 3,000 patients treated at Hospital del Mar

October 29, 2019

Science Daily/IMIM (Hospital del Mar Medical Research Institute)

The high levels of environmental noise we are subjected to in large cities can increase both the severity and consequences of an ischaemic stroke. More precisely, researchers from the Hospital del Mar Medical Research Institute (IMIM) and doctors from Hospital del Mar, together with researchers from the Barcelona Institute for Global Health (ISGlobal), CIBER in Epidemiology and Public Health (CIBERESP), and Brown University, in the United States, put the increased risk at 30% for people living in noisier areas. In contrast, living close to green areas brings down this risk by up to 25%. This is the first time that these factors have been analysed in relation to stroke severity. The study has been published in the journal Environmental Research.

The researchers looked at the influence of noise levels, air pollution (particularly suspended particles smaller than 2.5 microns; PM2.5), and exposure to green areas on nearly 3,000 ischaemic stroke patients treated at Hospital del Mar between 2005 and 2014. To do this, they used data from the Cartographic Institute of Catalonia, as well as models to analyse atmospheric pollutant levels, the noise map of Barcelona, and satellite images to define areas with vegetation. Also taken into account was the socioeconomic level of the place the patients lived.

Dr. Rosa María Vivanco, from the IMIM's Neurovascular Research Group and first author of the study, points out that the study gives us initial insight into how noise levels and exposure to green spaces influences the severity of ischaemic stroke. "We have observed a gradient: the more green spaces, the less serious the stroke. And the more noise, the more serious it is. This suggests that factors other than those traditionally associated with stroke may play an independent role in the condition," she explains. At the same time, Dr. Xavier Basagaña, one of the authors of the study and a researcher at ISGlobal, a centre supported by "la Caixa," stresses that "exposure to green spaces can benefit human health through various mechanisms. For example, it can reduce stress, encourage social interaction, and increase levels of physical activity." However, in this study no link was seen with atmospheric pollution. The researchers warn that one of the limitations of the work was the lack of variability in pollutant concentrations to which the study population is exposed. This made it difficult to draw conclusions, and they point out that more studies are needed in this field.

More noise, greater stroke severity

"Previous studies have demonstrated that living in places with high levels of air pollution or noise, or with fewer green areas, exposes the population to a higher risk of suffering an ischaemic stroke. This work broadens our knowledge in this field, showing that the place where we live affects not only the risk of suffering a stroke, but also its severity if it occurs," explains Dr Gregory A. Wellenius, from the Epidemiology Department at Brown University and final author of the study. In this sense, the results indicate that patients living in noisier areas presented more severe strokes on arrival at hospital.

The researchers have analysed the effects of stroke on neurological deficits, such as speech impairment and mobility, using the NIHSS (National Institute of Health Stroke Scale). "The severity of a stroke depends on various factors, including the extent of the brain injury, the specific area of brain affected, the subtype of stroke, the existence of associated risk factors (diabetes, atrial fibrillation, atherosclerotic load), and so on. The fact that we have demonstrated, in addition to all these factors, that environmental aspects like green spaces and urban noise levels affect the severity of a stroke and therefore our health, shows that this information must be taken into account by political and health planners," emphasises Dr. Jaume Roquer, head of the Neurology Service at Hospital del Mar, coordinator of the IMIM's Neurovascular Research Group, and one of the main authors of the work.

The researchers did not aim to determine which noise levels lead to increased risk, but rather to detect a gradient by comparing patients living in noisier areas with those living in quieter areas. Indeed, the World Health Organisation (WHO) recommends traffic noise limits of a maximum of 53 decibels during the day and 45 decibels at night. "The average noise level to which patients have been exposed, as well as the general population of the study area, requires reflection, as it is considerably above the WHO recommendations," points out Carla Avellaneda, an IMIM researcher and author of the work. The same researchers have already revealed that high levels of air pollution from diesel engines increase the risk of suffering atherothrombotic stroke by 20%.

Stroke

In Spain, stroke is the leading cause of death in women and the third ranked in men, and is estimated to affect 1 in 6 people throughout their lives (in 2012, it caused the death of 6.7 million people around the world, according to WHO data). In Catalonia there are 13,000 cases and 3,800 deaths from stroke each year. The two main types of stroke are haemorrhagic and ischaemic.

Ischaemic stroke is due to the obstruction of a blood vessel in the brain and accounts for 80-85% of all cases. This lack of blood flow in the affected area of the brain can lead to permanent damage. The risk of having a stroke is closely related to factors including age, smoking, high blood pressure, diabetes, obesity, a sedentary lifestyle and, as recently demonstrated, other factors like air pollution.

https://www.sciencedaily.com/releases/2019/10/191029103311.htm

Projected doubling of Americans living with dementia

Women are at much greater risk and shoulder the majority of costs

October 29, 2019

Science Daily/Milken Institute

The number of Americans living with Alzheimer's disease or other dementias will double to nearly 13 million over the next 20 years, according to the new Milken Institute report "Reducing the Cost and Risk of Dementia: Recommendations to Improve Brain Health and Decrease Disparities."

Milken Institute research estimates that by 2020, roughly 4.7 million women in the US will have dementia, accounting for nearly two-thirds of all people living with the condition.

The number of both women and men living with dementia is projected to nearly double by 2040, with the number of women projected to rise to 8.5 million, and the number of men expected to reach 4.5 million (up from 2.6 million in 2020), according to the report, which was released at the 2019 Milken Institute Future of Health Summit in Washington, D.C.

Over the next 20 years, the economic burden of dementia will exceed $2 trillion, with women shouldering more than 80 percent of the cumulative costs.

"Longer lifespans are perhaps one of the greatest success stories of our modern public health system," explains Nora Super, lead author of the report and senior director of the Milken Institute Center for the Future of Aging. "But along with this success comes one of our greatest challenges. Our risk of developing dementia doubles every five years after we turn 65; by age 85, nearly one in three of us will have the disease."

"With no cure in sight, we must double down on efforts to reduce the cost and risk of dementia," she added. "Emerging evidence shows that despite family history and personal genetics, lifestyle changes such as diet, exercise, and better sleep can improve health at all ages."

In collaboration with partners such as UsAgainstAlzheimer's, AARP and Bank of America, Super and her co-authors, Rajiv Ahuja and Kevin Proff, have developed detailed recommendations and goals for policymakers, businesses, and communities to improve brain health, reduce disparities, and ultimately change the trajectory of this devastating disease.

1) Promote strategies to maintain and improve brain health for all ages, genders, and across diverse populations

 2) Increase access to cognitive testing and early diagnosis

 3) Increase opportunities for diverse participation in research and prioritize funding to address health disparities

 4) Build a dementia-capable workforce across the care continuum

 5) Establish services and policies that promote supportive communities and workplaces for people with dementia and their caregivers

"As this important new report shows, dementia is one of the greatest public health challenges of our time," said Sarah Lenz Lock, SVP, Policy & Brain Health at AARP. "It also demonstrates that we have the power to create change, whether by helping consumers maintain and improve their brain health, advancing research on the causes and treatment of dementia, or supporting caregivers who bear so much of the burden of this disease. We at AARP look forward to working with the Milken Institute and other key partners to achieve these goals."

"Brain health broadens the fight against Alzheimer's to include everyone and is the key to defeating stigma, increasing early detection, speeding up research -- and ending this disease," said Jill Lesser, a founding board member of UsAgainstAlzheimer's. "This new look by the Milken Institute offers important recommendations and actions to help move us to an optimal system of brain health care in this country."

Among the breakthrough findings, new data have "unveiled key discoveries about the differences between men's and women's brains, and how they age. Moreover, women typically take on greater caregiver responsibilities than men. Women caregivers are more likely to be impacted financially and leave their jobs or miss work to care for a family member. And research demonstrates that spousal caregivers may be at a higher risk of cognitive impairment or dementia than non-caregivers."

"With this research, the Milken Institute has taken an important step to better understand the impacts of dementia on diverse populations," said Lorna Sabbia, Head of Retirement and Personal Wealth Solutions, Bank of America. "This study, together with our own research on life stages, women, health and wellness, plays a critically important role in our efforts to educate and provide guidance to individuals and families throughout their financial lives."

https://www.sciencedaily.com/releases/2019/10/191029084315.htm