How is Excess Body Fat Priming Our Brains for Mental Decline?

As today marks the 81st birthday of Krispy Kreme – an American doughnut company and coffeehouse chain based in Winston-Salem, North Carolina built off an ancient, secret cajun recipe – it seems a fitting day to talk about obesity, fat, and its effect on the brain.  Let’s start with “skinny fat”.

Sarcopenia, which is the loss of muscle mass, tends to happen naturally with age. So, in older people with sarcopenia, excess body fat may not be readily visible. But hidden fat, paired with muscle mass loss later in life, could predict Alzheimer’s risk, researchers warn, and Sarcopenic obesity may exacerbate the risk of other cognitive decline later in life.

A recent study — the results of which have been published in the journal Clinical Interventions in Aging — has found that sarcopenia and obesity (independently, but especially when occurring together) can heighten the risk of cognitive function impairments later in life.

The research was conducted by scientists at the Comprehensive Center for Brain Health at the Charles E. Schmidt College of Medicine of Florida Atlantic University in Boca Raton.

“Sarcopenia,” explains senior study author Dr. James Galvin, “has been linked to global cognitive impairment and dysfunction in specific cognitive skills including memory, speed, and executive functions.”

“Understanding the mechanisms through which this syndrome may affect cognition is important as it may inform efforts to prevent cognitive decline in later life by targeting at-risk groups with an imbalance between lean and fat mass.”

Dr. James Galvin

“They may benefit from programs addressing loss of cognitive function by maintaining and improving strength and preventing obesity,” he adds.

Beware sarcopenic obesity

The scientists analyzed health-related data collected from 353 participants — aged 69, on average — all of whom registered to take part in community-based studies on aging and memory.

To establish whether or not there was a link between sarcopenic obesity — that is, the presence of excess body fat in conjunction with muscle mass loss — and cognitive decline, the team assessed participants’ performance on tests evaluating cognitive function, including the Montreal Cognitive Assessment and animal-naming exercises.

Also, the participants’ muscle strength and mass were evaluated through grip strength tests and chair stands, and they also underwent body compositions assessments, which looked at muscle mass, body mass index (BMI), and the amount of body fat.

The researchers discovered that the participants with sarcopenic obesity had the poorest performance on cognition-related tests.  The next poorest performance on cognition tests was seen in people with sarcopenia alone, followed by participants who only had obesity.

Both when occurring independently and when occurring in concert, obesity and loss of muscle mass were linked with impaired working memory — which is the type of memory we use when making spontaneous decisions on a daily basis — as well as less mental flexibility, poorer orientation, and worse self-control.

Keep changes in body composition in check

The scientists explain that obesity could exacerbate the risk of cognitive decline through biological mechanisms that influence vascular health, metabolism, and inflammation.

Moreover, they warn that in people who already face impaired executive functioning, obesity might also impact energy resources through poor self-control that affects nutrition.

As for sarcopenia, the researchers note that it could influence brain mechanisms related to conflict resolution skills and selective attention.

Based on the study’s findings, Dr. Galvin and his colleagues are particularly concerned that a mix of sarcopenia and excess body fat in older adults could become a serious public health issue, so they believe that any significant changes in body mass composition should be closely monitored to prevent negative health outcomes.

“Sarcopenia either alone or in the presence of obesity, can be used in clinical practice to estimate potential risk of cognitive impairment,” notes study co-author Magdalena Tolea.

But such health issues can be kept under control, and the risks associated with them averted, she suggests.

“Testing grip strength by dynamometry can be easily administered within the time constraints of a clinic visit, and body mass index is usually collected as part of annual wellness visits,” concludes Tolea.

How Aging and Obesity Prime the Brain for Alzheimer’s

According to another new study, the effects of natural aging processes, combined with those of obesity and a poor diet, affect certain brain mechanisms, thereby boosting the risk of Alzheimer’s. The new study, conducted on mice, uncovered how a high-fat, high-sugar diet renders the aging brain more vulnerable to Alzheimer’s.

Alzheimer’s disease is a neurodegenerative condition that is characterized primarily by memory loss and impaired cognition.  Some risk factors for the development of this disease are aging and metabolic conditions such as obesity and diabetes.  However, many of the biological mechanisms underlying the onset and progression of this disease remain unknown.

This is despite the fact that our understanding of the predisposing risk factors is growing all the time.  Now, Rebecca MacPherson, Bradley Baranowski, and Kirsten Bott — of Brock University in Ontario, Canada — have conducted a study that has allowed them to uncover some more of the mechanics at play in the development of this type of dementia.

The team worked with aging mice to investigate how a high-fat, high-sugar (HFS) diet that fueled obesity might also prime the brain for neurodegeneration in this sample.  Their findings are described in a paper now published in the journal Physiological Reports.

How unhealthful diets impact the brain

Specifically, the researchers examined how an HFS diet, in conjunction with the effects of normal biological aging, would affect insulin signaling, which helps to regulate the amount of glucose (simple sugar) absorbed by muscles and different organs.

They also looked at how this obesity-inducing diet might alter biomarkers relating to inflammation and cellular stress.

To understand the impact of an HFS diet on aging mice, the research team put some mice on a regular type diet, while others were given food that had a high fat and sugar content.

After the mice had been fed their respective diets for a period of 13 weeks, the team looked for signs of inflammation and measured cellular stress levels in two brain areas associated with memory and cognitive behavior: the hippocampus and the prefrontal cortex.

The researchers also compared the effects of an HFS diet on the brains of aging rodents’ baseline measurements effected on the brains of younger mice.

They found older mice on an obesity-inducing diet had high levels of brain inflammation and cellular stress, as well as insulin resistance in parts of the hippocampus linked to the development of Alzheimer’s disease.

Although more markers of insulin resistance were observed in the prefrontal cortices of mice that had been on an HFS diet, inflammation status and cellular stress markers remained the same.

The study authors hypothesize that “region-specific differences between the prefrontal cortex and hippocampus in response to aging with an HFS diet [suggest] that the disease pathology is not uniform throughout the brain.”

Obesity boosts aging’s negative effect

Notably, the researchers also found that brain inflammation levels had also increased in the mice that had been on a regular diet, compared with baseline measurements.

The researchers note that this could be taken as evidence of aging’s role as an independent risk factor in Alzheimer’s. Obesity, they add, boosts the risk by affecting key mechanisms in the brain.

“This study,” they claim, “provides novel information in relation to the mechanistic link between obesity and the transition from adulthood to middle age and signaling cascades that may be related to [Alzheimer’s] pathology later in life.”

“These results add to our basic understanding of the pathways involved in the early progression of [Alzheimer’s] pathogenesis and demonstrate the negative effects of an HFS diet on both the prefrontal cortex and hippocampal regions.”

Every day, there are physicians in the HealthLynked system ready to help those combating obesity and care for Alzheimer and dementia patients  to help them live the best lives possible.  If someone you love is showing signs of memory loss beyond what might be considered normal for their age, or if too many donuts have made their way into your system, go to HealthLynked.com to connect and collaborate with any number of specialists at the ready.

 

Ready to get Lynked and get help?  Go to HealthLynked.com today to register for free!

 

Adapted from:

Cohut, Maria. ”Skinny fat’ linked to cognitive decline, study warns.” Medical News Today, Friday 6 July 2018

Cohut, Maria. ”Aging, obesity may prime the brain for Alzheimer’s.” Medical News Today, Monday 2 July 2018

 

Antibody helps detect protein implicated in Alzheimer’s, other diseases

May lead to novel ways to diagnose, monitor brain injury

by Tamara Bhandari•April 19, 2017

Researchers use mouse brains (above) to study ways to measure the brain protein tau, which plays a role in neurodegenerative diseases such as Alzheimer’s. A team led by scientists at Washington University School of Medicine in St. Louis has found a way to measure tau levels in the blood. The study, in mice and a small group of people, could be the first step toward a noninvasive test for tau

Damaging tangles of the protein tau dot the brains of people with Alzheimer’s and many other neurodegenerative diseases, including chronic traumatic encephalopathy, which plagues professional boxers and football players. Such tau-based diseases can lead to memory loss, confusion and, in some, aggressive behavior. But there is no easy way to determine whether people’s symptoms are linked to tau tangles in their brains.

Now, however, a team led by scientists at Washington University School of Medicine in St. Louis has found a way to measure tau levels in the blood. The method accurately reflects levels of tau in the brain that are of interest to scientists because they correlate with neurological damage. The study, in mice and a small group of people, could be the first step toward a noninvasive test for tau.

While further evaluation in people is necessary, such a test potentially could be used to quickly screen for tau-based diseases, monitor disease progression and measure the effectiveness of treatments designed to target tau.

The research is published April 19 in Science Translational Medicine.

“We showed that you can measure tau in the blood, and it provides insight into the status of tau in the fluid surrounding cells in the brain,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University School of Medicine in St. Louis.

Tau is a normal brain protein involved in maintaining the structure of neurons. But when tau forms tangles, it damages and kills nearby neurons.

“People with tau diseases have a wide range of symptoms because basically, wherever tau is aggregating, those parts of the brain are degenerating,” Holtzman said. “So if it’s in a memory area, you get memory problems. If it’s in a motor area, you get problems with movement.”

A blood-based screening test, likely years away, would be a relatively easy way to identify people whose symptoms may be due to problems with tau, without subjecting them to potentially invasive, expensive or complicated tests.

“We have no test that accurately reflects the status of tau in the brain that is quick and easy for patients,” Holtzman said. “There are brain scans to measure tau tangles, but they are not approved for use with patients yet. Tau levels can be measured in the cerebrospinal fluid that surrounds the brain and spinal cord, but in order to get to that fluid, you have to do a spinal tap, which is invasive.”

In the brain, most tau proteins are inside cells, some are in tangles, and the remainder float in the fluid between cells. Such fluid constantly is being washed out of the brain into the blood, and tau comes with it. However, the protein is cleared from the blood almost as soon as it gets there, so the levels, while detectable, typically remain very low.

Holtzman, postdoctoral researcher Kiran Yanamandra, PhD, and MD/PhD student Tirth Patel, along with colleagues from C2N Diagnostics, AbbVie, the University of California, San Francisco, and Texas Health Presbyterian Hospital, reasoned that if they could keep tau in the blood longer, the protein would accumulate to measurable levels. Allowing the protein to accumulate before measuring its levels would magnify – but not distort – differences between individuals, in the same way that enlarging a picture of a grain of sand alongside a grain of rice does not change the relative size of the two, but does make it easier to measure the difference between them.

The researchers injected a known amount of tau protein directly into the veins of mice and monitored how quickly the protein disappeared from the blood. The researchers showed that half the protein normally disappears in less than nine minutes. When they added an antibody that binds to tau, the half-life of tau was extended to 24 hours. The antibody was developed in the laboratories of Holtzman and Marc Diamond, MD, of the University of Texas Southwestern Medical Center, and is currently licensed to C2N Diagnostics, which is collaborating with the pharmaceutical company AbbVie in developing the technology.

To determine whether the antibody could amplify tau levels in an animal’s blood high enough to be measured easily, they injected the antibody into mice. Within two days, tau levels in the mice’s blood went up into the easily detectable range. The antibody acted like a magnifying glass, amplifying tau levels so that differences between individuals could be seen more easily.

Tau levels in people’s blood also rose dramatically in the presence of the antibody. The researchers administered the antibody to four people with a tau disease known as progressive supranuclear palsy. Their blood levels of tau rose 50- to 100-fold within 48 hours.

“It’s like a stress test,” Holtzman said. “We appear to be bringing out the ability to see what’s coming from the brain because the antibody amplifies differences by prolonging the time the protein stays in the blood.”

Measuring tau levels in the blood is only useful if it reflects tau levels in the brain, where the protein does its damage, the researchers said.

Both high and low levels of tau in the fluid that surrounds the brain could be a danger sign. Alzheimer’s and chronic traumatic encephalopathy both are associated with high levels of soluble tau, whereas progressive supranuclear palsy and other genetic tau diseases are thought to be associated with low levels.

To see whether elevated brain tau is reflected in the blood, the researchers treated mice with a chemical that injures neurons. The chemical causes tau to be released from the dying neurons, thereby raising tau levels in the fluid surrounding the cells. The scientists saw a corresponding increase of tau in the blood in the presence of the anti-tau antibody.

To lower tau levels, the researchers turned to genetically modified mice that, as they age, have less and less tau floating in their cerebrospinal fluid. Such mice at 9 months old had significantly lower tau levels in their blood than 3-month-old mice with the same genetic modification, again demonstrating the antibody’s ability to reflect levels of tau in the brain.

“It will be helpful in future studies to see if the measurement of tau in the blood following antibody treatment in humans reflects the state of tau in the brain,” Holtzman said.

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Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, Miller BL, Kerwin DR, Gallardo G, Stewart F, Finn MB, Cairns NJ, Verghese PB, Fogelman I, West T, Braunstein J, Robinson G, Keyser J, Roh J, Knapik SS, Hu Y, Holtzman DM. “Anti-tau antibody markedly increases plasma tau in mouse and man: Correlation with soluble brain tau.” Science Translational Medicine. April 19, 2017.

This work was supported by the National Institutes of Health (NIH), grant number NIH R01AG048678, C2N Diagnostics, the Tau Consortium and the JPB Foundation.

Holtzman and other authors on this paper developed the antibody used in this study and are inventors on a submitted patent “Antibodies to Tau” that is licensed by Washington University to C2N Diagnostics LLC. This patent subsequently was licensed to AbbVie. Yanamandra was a postdoctoral researcher at Washington University during the course of these studies and now is an employee at AbbVie.

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

MEDIA CONTACT
Diane Duke Williams, Associate Director for Media Relations

314-286-0111
williamsdia@wustl.edu
WRITER
Tamara Bhandari, Senior Medical Sciences Writer

Tamara Bhandari covers pathology, immunology, medical microbiology, cell biology, neurology, and radiology. She holds a bachelor’s degree in molecular biophysics and biochemistry and in sociology from Yale University, a master’s in public health/infectious diseases from the University of California, Berkeley, and a PhD in infectious disease immunology from the University of California, San Diego.

P314-286-0122
tbhandari@wustl.edu


Republished with permission.  See original and other great articles here.

Link between 2 key Alzheimer’s proteins explained | Targeting tau production may lead to treatment


by Tamara Bhandari•March 21, 2018

Alzheimer’s disease is characterized by clumps of two proteins – amyloid beta and tau – in the brain, but the link between the two has never been entirely clear. Now, researchers at Washington University School of Medicine in St. Louis have shown that people with more amyloid in the brain produce more tau, which could lead to new treatments for the disease based on targeting the production of tau.

It’s a paradox of Alzheimer’s disease: Plaques of the sticky protein amyloid beta are the most characteristic sign in the brain of the deadly neurodegenerative disease. However, many older people have such plaques in their brains but do not have dementia.

The memory loss and confusion of Alzheimer’s instead is associated with tangles of a different brain protein – known as tau – that show up years after the plaques first form. The link between amyloid and tau has never been entirely clear. But now, researchers at Washington University School of Medicine in St. Louis have shown that people with more amyloid in their brains also produce more tau.

The findings, available March 21 in the journal Neuron, could lead to new treatments for Alzheimer’s, based on targeting the production of tau.

“We think this discovery is going to lead to more specific therapies targeting the disease process,” said senior author Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology.

Years ago, researchers noted that people with Alzheimer’s disease have high levels of tau in the cerebrospinal fluid, which surrounds their brain and spinal cord. Tau – in the tangled form or not – is normally kept inside cells, so the presence of the protein in extracellular fluid was surprising. As Alzheimer’s disease causes widespread death of brain cells, researchers presumed the excess tau on the outside of cells was a byproduct of dying neurons releasing their proteins as they broke apart and perished. But it was also possible that neurons make and release more tau during the disease.

In order to find the source of the surplus tau, Bateman and colleagues decided to measure how tau was produced and cleared from human brain cells.

Along with co-senior author Celeste Karch, PhD, an assistant professor of psychiatry, and co-first authors Chihiro Sato, PhD, an instructor in neurology, and Nicolas Barthélemy, PhD, a postdoctoral researcher, the researchers applied a technique known as Stable Isotope Labeling Kinetics (SILK). The technique tracks how fast proteins are synthesized, released and cleared, and can measure production and clearance in models of neurons in the lab and also directly in people in the human central nervous system.

Using SILK, the researchers found that tau proteins consistently appeared after a three-day delay in human neurons in a laboratory dish. The timing suggests that tau release is an active process, unrelated to dying neurons.

Further, by studying 24 people, some of whom exhibited amyloid plaques and mild Alzheimer’s symptoms, they found a direct correlation between the amount of amyloid in a person’s brain and the amount of tau produced in the brain.

“Whether a person has symptoms of Alzheimer’s disease or not, if there are amyloid plaques, there is increased production of this soluble tau,” Bateman said.

The findings are a step toward understanding how the two key proteins in Alzheimer’s disease – amyloid and tau – interact with each other.

“We knew that people who had plaques typically had elevated levels of soluble tau,” Bateman said. “What we didn’t know was why. This explains the why: The presence of amyloid increases the production of tau.”

Tau is strongly linked to brain damage, so overproduction of the protein could be a critical step in the development of Alzheimer’s, and reducing tau’s production may help treat the disease, the researchers said.

“These findings point to an important new therapeutic avenue,” Karch said. “Blocking tau production could be considered as a target for treatment for the disease.”

Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TLS, Miller TM, Karch CM and Bateman RJ. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. March 21, 2018.

This work was supported by the National Institutes of Health (NIH), grant number R01NS095773, R01NS078398, K01 AG046374, K01 AG053474, P30DK056341, P01AG003991, UL1TR000448, P30NS098577, P50AG005681, and P01AG026276; Brightfocus Foundation, grant number A2014384S; the National Institute of Neurological Disorders and Stroke, grant numbers P01NS080675 and P30NS098577; Tau SILK Consortium (AbbVie, Biogen, and Eli Lily); Metlife Foundation; ALS Association; DIAN-TU; Hope Center for Neurological Disorders; The Foundation for Barnes-Jewish Hospital; Kanae Foundation for the Promotion of Science; McDonnell Science Grant for Neuroscience; the Tau Consortium; the Knight Alzheimer’s Disease Research Center; Coins for Alzheimer’s Research Trust; Alzheimer’s Association; and resources provided by Washington University Biomedical Mass Spectrometry Research Facility (NIH P41GM103422), Diabetes Research Center (NIH P30DK020579), and the Nutrition Obesity Research Center (NIH P30DK056341).

Washington University School of Medicine‘s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

MEDIA CONTACT
Judy Martin Finch, Director of Media Relations

314-286-0105
martinju@wustl.edu
WRITER
Tamara Bhandari, Senior Medical Sciences Writer

Tamara Bhandari covers pathology, immunology, medical microbiology, cell biology, neurology, and radiology. She holds a bachelor’s degree in molecular biophysics and biochemistry and in sociology from Yale University, a master’s in public health/infectious diseases from the University of California, Berkeley, and a PhD in infectious disease immunology from the University of California, San Diego.

314-286-0122
tbhandari@wustl.edu


In honor of ALzheimers and Brain Awareness Month, this has been reproduced with permission.