Risk gene for Alzheimer’s has early effects on the brain

A genetic predisposition to late-onset Alzheimer’s disease affects how the brains of young adults cope with certain memory tasks. Researchers from the German Center for Neurodegenerative Diseases (DZNE) and the Ruhr-Universität Bochum report on this in the scientific journal Current Biology. Their findings are based on studies with magnetic resonance imaging in individuals at the age of about 20 years. The scientists suspect that the observed effects could be related to very early disease processes.

The causes for Alzheimer’s in old age are only poorly understood. It is believed that the disease is caused by an unfavorable interaction of lifestyle, external factors and genetic risks. The greatest genetic risk factor for late-onset Alzheimer’s disease stems from inherited mutations affecting “Apolipoprotein E” (ApoE), a protein relevant for fat metabolism and neurons. Three variants of the ApoE gene are known. The most common form is associated with an average risk for Alzheimer’s. One of the two rarer variants stands for an increased risk, and the other for a reduced risk.

“We were interested in finding out whether and how the different gene variants affect brain function. That is why we examined the brains of young adults in the scanner while they had to solve a task that challenged their memory,” explained Dr. Hweeling Lee, who led the current study at the DZNE in Bonn.

Distinguishing similar events

The group of study participants comprised of 82 young men and women. They were on average 20 years old, and all of them were university students considered to be cognitively healthy. According to their genotype for ApoE, 33 of them had an average, 34 an increased and 15 a reduced risk of developing Alzheimer’s disease at a late age. During the study in the brain scanner, all individuals were presented with more than 150 successive images displayed on a monitor. These were everyday objects such as a hammer, a pineapple or a cat. Some pictures were repeated after a while, but sometimes the position of the displayed objects on the screen had changed. The study participants had to identify whether an object was “new” or had been shown before—and if so, whether its position had shifted.

“We tested the ability to distinguish similar events from one another. This is called pattern separation,” said Hweeling Lee. “In everyday life, for example, it’s a matter of remembering whether a key has been placed in the left or right drawer of a dresser, or where the car was parked in a parking garage. We simulated such situations in a simplified way by changing the position of the depicted objects.”

High-resolution through modern technology

Simultaneously to this experiment, the brain activity of the volunteers was recorded using a technique called “functional magnetic resonance imaging”. Focus was on the hippocampus, an area only a few cubic centimeters in size, which can be found once in each brain hemisphere. The hippocampus is considered the switchboard of memory. It also belongs to those sections of the brain in which first damages occur in Alzheimer’s disease.

When measuring brain activity, the scanner was able to show its full potential: It was an “ultra-high field tomograph” with a magnetic field strength of seven Tesla. Such devices can achieve a better resolution than brain scanners usually used in medical examinations. This enabled the researchers to record brain activity in various sub-fields of the hippocampus with high precision. “Up to now, there were no comparable studies with such level of detail in ApoE genotyped participants. This is a unique feature of our research,” said Hweeling Lee.

No differences in memory performance

There were no differences between the three groups of subjects with regard to their ability for pattern separation. “All study participants performed similarly well in the memory test. It did not matter whether they had an increased, reduced or average risk for Alzheimer’s disease. Such results are certainly to be expected in young healthy people,” said Nikolai Axmacher, Professor of Neuropsychology at the Ruhr-Universität Bochum, who was also involved in the current study. “However, there were differences in brain activity. The different groups of study participants activated the various subfields of the hippocampus in different ways and to varying degrees. Their brains thus reacted differently to the memory task. In fact, we saw differences in brain activation not only between people with average and increased risk, but also between individuals with average and reduced risk.”

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Smartphones can predict brain function associated with anxiety and depression

Information on social activity, screen time and location from smartphones can predict connectivity between regions of the brain that are responsible for emotion, according to a study from Dartmouth College.

In the research, data from phone usage was analyzed alongside results from fMRI scans to confirm that passively collected information can mirror activity in the brain linked to traits such as anxiety. Predictions based solely on the phone data matched the brain scans with 80 percent accuracy.

The study, presented at ACM UbiComp, an annual conference on pervasive and ubiquitous computing, represents the first time researchers have been able to predict connectivity between specific brain regions solely based on passive data from smartphones.

“Simple information about how someone is using their smartphone can provide a peek into the complex functioning of the human brain,” said Mikio Obuchi, a Ph.D. student in the Department of Computer Science at Dartmouth and lead author of the study. “Although this research is just beginning, combining data from smartphones—rather than fMRI alone—will hopefully accelerate research to understand better how the human brain works.”

According to the research, how often and how long an individual uses their phone provides information about the functioning between the ventromedial prefrontal cortex and the amygdala—two key centers of the brain related to emotional state.

The ventromedial prefrontal cortex is responsible for self-control, decision making, and risk evaluation. The amygdala triggers the fight or flight response and helps individuals determine the emotions of others.

In addition to data on social activity, screen time and location, information on exercise and sleep patterns was also collected for the study.

The research found that more screen time, regular exercise, earlier bedtimes, higher social interaction and certain location patterns passively inferred from phone data matched a state of higher functional connectivity between the brain regions. This increased activity indicates a more positive emotional state.

“We are not suggesting that phones should replace technology like fMRI, but they can help individuals and health providers learn more about behavior patterns from everyday observations,” said Jeremy Huckins, a lecturer on psychological and brain sciences at Dartmouth and a co-author of the study.

The research result aligns with clinical evidence showing that stronger connectivity between the ventromedial prefrontal cortex and the amygdala to be associated with lower levels of anxiety and depression. Weaker functional connectivity, on the other hand, represents a more negative emotional state.

Anonymous fMRI data from volunteer participants were placed into two categories divided by low and high brain connectivity levels. By matching phone data against the fMRI results the researchers were able to predict which research subjects had higher or lower connectivity between brain regions with 80 percent accuracy.

According to the research team, the use of passive information from a smartphone can help eliminate the subjectivity that often complicates other information-gathering techniques on emotional well-being such as personal interviews and self-reporting on questionnaires.

The phone information allowed researchers to predict the emotional state of individuals at any given time without intrusive data collection. The data also support predictions of the long-term emotional traits in individuals.

“Hopefully, this study shows how mobile sensing can provide deep longitudinal human behavioral data to complement brain scans,” said Andrew Campbell, the Albert Bradley 1915 Third Century Professor of computer science at Dartmouth and the senior researcher on the study. “This could offer new insights into the emotional well-being of subjects that would just not be possible without continuous sensing.”

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Mum's pain as son diagnosed with cancer weeks after twin died from brain tumour

When Jack Parton started experiencing back pain and tiredness, doctors initially thought it was due to grief.

The 12-year-old lost his twin brother Ben to a brain tumour just a few weeks before.

But just a fortnight after Ben’s funeral in December last year, the family were given the heartbreaking news that Jack had leukaemia – a type of blood cancer.

The boys’ mum, Julie, 51, from Cannock, Staffordshire, said: It’s almost impossible to put into words how horrendous this has been.

‘Having gone through everything with Ben and, just as we were grieving his loss, it was a hammer blow to find out only two weeks after his funeral that Jack was also fighting cancer.’

The boys were revising for their SATs in March last year when Ben started to complain about headaches.

Soon he was also vomiting but his mum thought he’d caught the sickness bug going around school. When it didn’t get better, she took him to hospital.’

She explained: ‘We were waiting for an appointment at the opticians but I took him to the urgent care clinic at Walsall Manor Hospital where he was checked over and we were reassured to be told he had gastroenteritis.

‘The sickness would stop and start again a couple of days later and by mid-April Ben had lost quite a bit of weight and was struggling to move his right arm so it was back to urgent care where I was told, once again, it was a stomach bug. We were given antacid medication and told to seek a paediatric referral through our GP.

‘I felt everyone was dragging their feet and, with Ben still poorly, I took him to A&E once again where we were told his blood results were fine and we were sent on our way.’

Just four days later, Ben collapsed and the family had to call an ambulance. He was given a CT scan, which showed he had a brain tumour.

24 hours later, he had surgery to remove the tumour and a biopsy revealed he had a grade 4 glioblastoma multiforme (GBM). Sadly, his family where told just 20% of patients live beyond five years of their diagnosis.

He was scheduled to have radiotherapy four weeks later but a scan before showed the tumour had already grown back, which meant more surgery.

Ben started 30 sessions of radiotherapy on 3 July followed by four cycles of chemotherapy in September, but by the second round, it was clear the treatment wasn’t working.

Sadly, the cancer spread and Ben passed away eight months after his diagnosis in December 2019.

The heartbroken family prepared to lay Ben to rest but at the same time, Jack started to feel very tired.

Doctors thought it might be the post traumatic stress of losing his twin but genetic testing raised the alarm.

Julie explained: ‘During Ben’s many tests it had been discovered that he had a genetic disorder which meant his TP53 gene, a tumour suppressor, was faulty.

‘And it was during screening to see if Jack was similarly affected that the alarm bells started to ring. We were told that his symptoms were not neurological so, mercifully, he didn’t have a brain tumour.

‘However, when we were immediately recalled to the hospital and told to bring an overnight bag, I was so scared.’

Jack had to have treatment at Birmingham Children’s Hospital, where his brother had gone just the year before.

Amazingly, Jack is now cancer-free but will have to stay on chemotherapy tablets for two-and-a-half years to stop it coming back.

Julie said: All things considered, Jack is doing well although some days are incredibly tough. He misses Ben so much and would give anything for them to be on PlayStation together.’

She is campaigning with the charity Brain Tumour Research and is urging people to make a difference by signing a petition to increase the national investment into brain tumour research to £35 million a year which would bring parity of funding with other cancers such as leukaemia, breast and prostate.

‘Thanks to the investment in research, Jack and other leukaemia patients now have hope of a cure. Ben was not so lucky, he never really stood a chance,’ Julie said.

‘Historically, just 1% of the national spend on cancer research has been allocated to brain tumours and treatment options remain very limited and survival rates very poor.’

According to Brain Tumour Research, more children and adults under the age of 40 die of a brain tumour than any other cancer

Since national cancer spend records began in 2002, £680 million has been invested in breast cancer, yet only £96 million in brain tumours – a difference of £35 million a year over 17 years.

Brain Tumour Research funds sustainable research at dedicated centres in the UK. It also campaigns for the Government and the larger cancer charities to invest more in research into brain tumours.

The charity is calling for a national annual spend of £35 million in order to improve survival rates and patient outcomes in line with other cancers such as breast cancer and leukaemia.

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Bacteria in the gut have a direct line to the brain

With its 100 million neurons, the gut has earned a reputation as the body’s “second brain”—corresponding with the real brain to manage things like intestinal muscle activity and enzyme secretions. A growing community of scientists are now seeking to understand how gut neurons interact with their brain counterparts, and how failures in this process may lead to disease.

Now, new research shows that gut bacteria play a direct role in these neuronal communications, determining the pace of intestinal motility. The research, conducted in mice and published in Nature, suggests a remarkable degree of communication between our nervous system and the microbiota. It may also have implications for treating gastrointestinal conditions.

“We describe how microbes can regulate a neuronal circuit that starts in the gut, goes to the brain, and comes back to the gut,” says Rockefeller’s Daniel Mucida, associate professor and head of the Laboratory of Mucosal Immunology. “Some of the neurons within this circuit are associated with irritable bowel syndrome, so it is possible that dysregulation of this circuit predisposes to IBS.”

The work was led by Paul A. Muller, a former graduate student in the Mucida lab.

How microbes control motility

To understand how the central nervous system senses microbes within the intestines, Mucida and his colleagues analyzed gut-connected neurons in mice that lacked microbes entirely, so-called germ-free mice that are raised from birth in an isolated environment, and given only food and water that has been thoroughly sterilized. They found that some gut-connected neurons are more active in the germ-free mice than in controls and express high levels of a gene called cFos, which is a marker for neuronal activity.

This increase in neuronal activity, in turn, causes food to move more slowly than usual through the digestive tract of the mice. When the researchers treated the germ-free mice with a drug that silences these gut neurons, they saw intestinal motility speed up.

It’s unclear how the neurons sense the presence of gut microbes, but Mucida and his colleagues found hints that the key may be a set of compounds known as short-chain fatty acids, which are made by gut bacteria. They found that lower levels of these fatty acids within the guts of mice were associated with greater activity of the gut-connected neurons. And when they boosted the animal’s gut levels of these compounds, the activity of their gut neurons decreased. Other microbial compounds and gut hormones that change with the microbiota were also found to regulate neuronal activity, suggesting additional players in this circuit.

Neurons in control

Further experiments revealed a conundrum, however. The scientists saw that the particular type of gut-connected neurons activated by the absence of microbes did not extend to the exposed surface of the intestines, suggesting that they cannot sense the fatty acid levels directly.

So Mucida and his colleagues decided to trace the circuit backwards and found a set of brainstem neurons that show increased activity in the germ-free mice. When the researchers manipulated control mice to specifically activate these same neurons, they saw an increase in the activity of the gut neurons and a decrease in intestinal motility.

The researchers continued to work backwards, next focusing their attention on the sensory neurons that send signals from the intestines to the brainstem. Their experiments revealed these sensory neurons extended to the interface of areas of the intestine that are exposed to high-levels of microbial compounds, including fatty acids. They turned off these neurons, to mimic what happens in germ-free mice that lack the fatty acids, or associated gut signals, and observed activated neurons in the brainstem, as well as activation of the gut neurons that control intestinal motility.

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Measuring the complexity of the aging brain

An international collaboration between the Center for Healthy Brain Aging (CHeBA) and Beihang University in China has researched differential longitudinal changes in structural complexity and volumetric measures in community-dwelling older individuals.

The research analyzed the brain scans of community-dwelling older individuals aged 70-90 without dementia, using data from CHeBA’s Sydney Memory & Aging Study.

The findings, published in Neurobiology of Aging discovered that a measure of “complexity” of the brain is more sensitive to brain changes over time than more conventional measures such as cortical thickness or cortical volumes.

To understand the concept, Group Leader of CHeBA’s Neuroimaging Group and co-author on the research, Associate Professor Wei Wen asks us to consider how we measure and compare the geometric complexity of two objects.

“There are many ways, depending on what you want to measure,” says Associate Professor Wen. “Natural and biological morphologies are irregular.”

“Compared with Euclidean geometry, a term used to denote standard geometry such as width, length or volume and thickness, mother nature exhibits not simply just a higher degree but entirely a different level of complexity.”

An example, according to Associate Professor Wen, is if you zoom in from a satellite image of the coastline of Australia, you will see increasing amount of detail altering from a simple curve to a clear representation of bays, inlets and lagoons.

“Such ‘zooming-in’ can be infinite and the complexity of the coastline will continue to increase so long as our satellite has such spatial resolution,” he says.

Fractal analysis is one of the methods in describing and quantifying the morphological complexity in magnetic resonance imaging (MRI).

“To investigate the relationship between the complexity measure, which is indexed as fractal dimensionality (FD), and the traditional Euclidean metric, such as volume and thickness, of the brain in older age, we analyzed MRI scans of 161 community-dwelling, non-demented individuals aged 70-90 years at baseline and at their 2-year and 6-year follow-ups,” said Associate Professor Wen.

“We quantified changes of neuroimaging metrics in cortical lobes and subcortical structures, and investigated the age, sex, hemisphere and education effects on FD.”

FD showed significant age-related decline in all brain structures, and its trajectory was best modeled quadratically, i.e. it accelerated in later years, in bilateral frontal, parietal, and occipital lobes, as well as in bilateral subcortical structures such as hippocampus.

According to Professor Wei Wen the findings suggest that FD is reliable yet shows a different pattern of decline compared to volumetric measures.

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Adults with Alzheimer’s risk factors show subtle alterations in brain networks despite normal cognition

Researchers at McGill University and the Douglas Mental Health University Institute, in collaboration with the StoP-AD Center, have published a new paper in the Journal of Alzheimer’s Disease, examining how a known genetic risk factor for late-onset Alzheimer’s disease (AD) influences memory and brain function in cognitively intact older adults with a family history of AD.

For their study, the researchers looked at a specific gene, called apolipoprotein E (APOE), which has three allelic variants: e2, e3 and e4. Of these genetic variants, previous studies have shown adults with a single APOE e4 (+APOEe4) gene are at higher risk of developing AD. In this study, Drs. Sheida Rabipour, Maria Natasha Rajah and collaborators used functional magnetic resonance imaging (fMRI) to explore whether having a +APOEe4 genotype altered brain activity during memory task performance in older adults who may be at risk of developing AD.

“It turns out that the +APOEe4 variant, most strongly associated with AD development, doesn’t directly affect memory performance or brain activity in cognitively intact older adults,” explains Dr. Rabipour, a postdoctoral researcher in the lab of Dr. Rajah, and the study’s first author. “Rather, +APOEe4 seems to influence the brain regions and systems that older at-risk adults activate to support successfully remembering past events.”

Specifically, older adults with +APOEe4 use different brain regions, such as the parietal cortex, to support successful memory encoding, compared to adults without this genetic risk factor. In contrast, older adults without the APOEe4 genetic risk for AD use traditional memory-related brain regions, such as the medial temporal lobes and prefrontal cortex, to support successful memory encoding. The findings suggest that the role of +APOEe4, when examined over and above the influence of family history, is subtle, and affects the correlation between brain activity and memory performance.

Drawing on existing cohort for data

To complete their study, the researchers examined the influence of +APOEe4 in 165 healthy older adults from the PREVENT-AD cohort, factoring out age and family history, which are also important risk factors for AD. The team used a powerful multivariate analytical approach, enabling them to objectively disentangle people’s general sense of familiarity from specific recollection of an event and its associated context.

“We used a robust data-driven method that does not focus on any particular brain region, but rather examines the whole brain patterns of activity across the different stages and processes required to complete the memory task we designed,” says Dr. Rabipour.

The team was able to identify a distinct relationship between performance and brain activity patterns for recognition memory, even in cognitively normal older adults, based on +APOEe4 genotype. “In other words, even though all our participants were cognitively normal and performed well on the memory task, we were still able to detect a difference in the brain systems supporting memory function based on having a copy of +APOEe4,” notes Dr. Rabipour.

Moving forward

The findings of the study show that there are differences in the relationships between recognition and associated brain activity patterns based on genetic risk for AD and that these differences are measurable even in cognitively normal older adults, when accounting for family history of AD. Additionally they show that the tasks used to measure memory performance are important to consider when examining the nuances between different types of memory and how they may be affected by AD risk factors. Finally, the results suggest that family history and APOE genotype should be considered separately when examining AD risk.

“Understanding the ways in which different genotypes influence—or don’t influence—behavior and brain activity has important implications on the way we design treatments for AD-related memory impairments as well as our approach to preventing and delaying AD development,” explains Dr. Rabipour. “Using our task, we were also able to support a leading theory that memory systems for general familiarity are distinct from those that underlie detailed recollection of a past event. This could imply different approaches to diagnosing and treating conditions that impact one memory system compared to the other and may also help develop tools or strategies to enhance these types of memory as we age.”

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Ability to eliminate spent proteins influences brain aging and individual life span

Aging is the main risk factor for dementia and Parkinson’s disease. As age progresses, toxic protein aggregates pile up in the brain and impair neuronal function. But why does that happen? An international team of scientists coordinated by the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) (Jena, Germany) and the Scuola Normale Superiore (Pisa, Italy) found answers by studying the brain of the turquoise killifish (Nothobranchius furzeri) brains. They delineate a timeline of molecular events during aging that is triggered by the early reduction of proteasome activity and culminates in aggregates formation. Remarkably, fish that preserve proteasome levels during aging live longer.

Protein homeostasis refers to the processes involved in the synthesis, folding, trafficking, location, and degradation of the entire set of proteins in the cell—the proteome. This complex network regulation is essential for all living organisms and its disturbance contributes to age-related diseases and influence life span.

Neurodegenerative diseases such as Alzheimer’s, ALS, and Parkinson’s are devastating conditions characterized by deterioration of neurons (nervous system cells) and/or spinal cord. These diseases have common features: they usually strike in mid to late-life and are accompanied by an accumulation of protein aggregates inside neurons. As a consequence of the increased age of our population, the percentage of people affected by these diseases increases steadily. Therefore, finding treatments to limit the damage of neurodegeneration is a pressing medical and societal need, and it critically depends on the understanding of how and why protein aggregates form during brain aging.

An international team led by researchers from the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI) in Jena, Germany and the Scuola Normale Superiore in Pisa, Italy, together with the Centre for Misfolding Diseases in Cambridge, UK and the National Hellenic Research Foundation in Athen, Greece, has now used state-of-the-art transcriptomic and proteomic methods to investigate the chain of molecular events that lead to loss of protein homeostasis during brain aging. The researchers used Nothobranchius furzeri (killifish) as a model of aging to study mechanisms triggering protein homeostasis dysfunction. This fish species is the shortest-lived vertebrate bred under laboratory conditions—they have a life span of only 3—12 months! Age-dependent processes are exacerbated in this species, making it easier to detect changes in the concentration of RNAs and proteins, as compared to other model organisms. Also, aging induces in this fish pathological changes that mimic those typical of human aging, making it a practical vertebrate system for studying age-related neurodegenerative disorders.

During aging, proteins and RNAs become uncorrelated

“In order to identify the molecular events in the aging process that are responsible for the loss of protein homeostasis during brain aging, we used mass spectrometry-based proteomics in combination with RNA sequencing and analyzed protein aggregates in the brains of killifish of different ages,” says Dr. Alessandro Ori. The researchers analyzed brains of killifish from three different age groups: young sexually mature fish (5 weeks after hatching, wph), adult fish without aging characteristics (12 wph) and old fish that already showed signs of neurodegeneration (39 wph).

Messenger RNAs are used by the ribosome in the cell to synthetize proteins, which are biologically active molecules. “Measuring RNAs levels is easier that measuring protein levels and scientists very often measure changes in RNA levels under the assumption that the abundance of the corresponding proteins will change in a similar direction. The first result of our study is that during aging almost half of the proteins are regulated in opposite direction with respect to their corresponding RNA. This was a real surprise!” said Prof. Alessandro Cellerino from the Scuola Normale Superiore in Pisa, Italy. The study has now been published in the journal Molecular Systems Biology.

Age-related loss of the stoichiometry of essential protein complexes

“When comparing the data for the different age groups, we found that almost half of the approximately 9000 proteins that we managed to quantify are affected by aging,” says Dr. Alessandro Ori, group leader at FLI. These age-related changes result in abnormal regulation of proteins (subunits) that compose macromolecular protein complexes, the types of machinery responsible for all cellular activities. Protein complexes are built by different proteins that need to be assembled in specific ratios. Our cells have mechanisms to guarantee the proper building of these complexes by regulating the precise (stoichiometric) number of specific subunits. This tightly regulated process, however, is impaired in aging.

As Dr. Ori further explains, “there is a progressive loss of stoichiometry of protein complexes during aging, mainly affecting the ribosomes, which is one of the most important protein complexes in the cell, responsible for producing all other proteins.” The researchers demonstrated that ribosomes do not get adequately formed in old brains and aggregate, potentially influencing vital functions in the cell. Aggregation of ribosomes is not exclusive to killifish but also happens in mice, suggesting it is a conserved feature of brain aging.

Decrease in proteasome activity as an early sign of brain aging

“Ribosome aggregation is something devastating for cell survival. We wanted to understand what is causing it. More than that, we tried to find an early event during aging that triggers aggregates formation”, explains Dr. Erika Kelmer Sacramento, one of the first authors of the study that focused on the proteasome. Proteasomes are complexes of protein molecules that digest and recycle old or defective proteins and are an essential part of the protein homeostasis network (“garbage chipper” of the cell). The authors were able to show that proteasome activity is reduced early and progressively during the course of adult life and causes loss of protein complexes stoichiometry. They induced a reduction of proteasome activity during early adult life of the killifish using a specific drug for just four days and observed a premature aging signature including disrupted ratios of several protein complexes.

Low proteasome activity—short life span?

“As aging is the result of a chain of interconnected progressive events, it has been difficult to identify its early drivers. Decrease of proteasome activity is an early sign of brain aging, but is it relevant for aging of the entire organism? To answer this question, we correlated individual variations in proteasome activity with individual variations in lifespan,” explains Prof. Cellerino. So the team also compared the gene expression data of more than 150 killifish with their lifespan. The analysis showed that the individuals’ lifespan could be predicted based on changes in the expression of genes encoding for proteasomal proteins: fish that showed a greater decrease in proteasome transcripts at the beginning of life lived considerably shorter than fish able to maintain or increase proteasome expression. This finding supports the hypothesis that the reduction of proteasome activity is an early driver of aging in vertebrates.

“The FLI has made large investments in developing the killifish as a biological model. Our results show that this investment was well placed. The killifish revealed novel molecular aspects of aging: we were able to show for the first time that the maintenance of proteasome activity is an important factor for the correct stoichiometry of protein complexes involved in key biological functions such as protein synthesis, degradation, and energy production and ultimately for lifespan determination. These comprehensive results on RNA and protein regulation represent also a public resource that can be mined by scientific community, as it was the case for the genomic, transcriptomic and epigenetic resources previously generated at the FLI,” says Prof. Cellerino summarizing the most important results.

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Good memory to old age – and Why some are long mentally fit – Naturopathy naturopathy specialist portal

Differences in memory performance in old age

Some people show up to a high age has a remarkable memory performance, while others suffer a considerable loss of memory. Now, it was investigated why these differences in memory performance occur in the progressive age and how it can be prevented.

In a study at Stanford University, was to determine which factors have an influence on how well we can remember in old age. The results of the study were published in the English journal “eLife”.

After the memory automatically?

Even in totally healthy people a discount is the end of memory is often an expected part of aging. But such a weakening memory is by no means inevitable. Some people have also in the upscale age is still a very good memory.

Differences in memory performance were investigated

“The study of these differences between individuals is crucial for the understanding of the complexity of brain aging, including the question of how resilience and durability can be promoted,” says study author Alexandra Trelle, at Stanford University, in a press release.

How did the memory retrieval processes of older people?

Based on studies, which had focused on younger people, the research group studied in the framework of the Stanford Aging and Memory Study of memory in healthy, older adults. The Team found that the memory retrieval processes in the brains of older adults can look very similar, as previously in the brains of young adults of the processes observed. In people with greater difficulties to remember, were the instructions on these processes, however, are considerably smaller.

Activity of the whole brain was measured

Through a better understanding of memory function in older adults will one day say, hopefully, earlier and more precise prior allows, when memory failures occur, and when there is an increased risk for dementia is present, report the researchers.

What was studied?

For the study of one hundred part were participants between the ages of 60 and 82 years, their brains using magnetic resonance imaging scanning while they viewed words paired with pictures of famous people and places. These Participants were then testing with words asked during a Memory to recall the associated picture. The analyses of the MRI images of the Gehrins focused not only on the extent of the activity, but also on the memory information contained in the Patterns of brain activity.

What was done the memory test?

With the memory test, the ability should be evaluated, to remember certain associations between elements of an event. This is a Form of memory, which is often influenced disproportionately by the aging process, report researchers.

Memory is a neural time travel

The research group found that the brain processes that support memory in older adults are similar to those in younger groups of the population. If people remember, there is an increase in hippocampal activity, along with the recovery of activity patterns in the cortex, were present when the event was first experienced. This means that the journey includes Remind a quasi-neural time, which includes the Repeat of Patterns that were previously established in the brain.

What has been the role of the Hippo-campus activity?

The Team was able to actually say on the basis of the information contained in Patterns of brain activity to predict whether a Person would remember a specific time or not. The researchers found that memory declined in age, on average. It was noticeable, however, regardless of age, with greater hippocampal activity, and recurrence was associated in the cortex with better memory performance. This was true not only for the during the MRI Scans carried out memory test, but also for memory tests, which were carried out on a different day of the study.

What is the goal of future research?

It is clear that the functional magnetic resonance imaging of brain activity during memory retrieval find stable differences between individuals and on the health of the brain may indicate, reports the researchers. The current study lay the Foundation for many future studies of the memory of older adults in the cohort of the Stanford Aging and Memory Study. The ultimate goal was to develop new and sensitive instruments to identify persons at increased risk for Alzheimer’s disease, before significant memory loss occurs. (as)

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Study shows patients with hemorrhagic brain disease have disordered gut microbiomes

A new study shows that people with a rare genetic disease that causes bleeding in the brain have gut microbiomes distinct from those without the disease. Moreover, it is the molecules produced by this bacterial imbalance that cause lesions to form in the brains of these patients.

The results are the first in any human neurovascular disease. They have implications both for treating the disease and in examining other neurovascular diseases that could be affected by a person’s gut microbiome.

The study was led by investigators at University of Chicago Medicine and published May 27 in Nature Communications. It examined the gut bacteria of patients with cavernous angioma (CA), a disease where blood vessel abnormalities develop in the brain and cause strokes, seizures and serious neurologic complications. The disease is caused by a genetic mutation in the lesion —which may be inherited or occurs sporadically—and its severity and course vary widely among patients.

UChicago is a leader in studying this disease. It has been designated as a cavernous angioma center of excellence and treats patients with the condition from all over the world.

Investigators had hints that the disease could be affected by the gut microbiome: Senior author Issam Awad, MD, the John Harper Seeley Professor of Neurosurgery and Director of Neurovascular Surgery at UChicago Medicine, was a partner in a previous study in mice, which showed that the cells that lined the blood vessels of the brain reacted to the animals’ gut bacteria.

“The implications of that were very big,” he said. “But we didn’t know if this concept of a unique microbiome that favors the development of lesions would be true in human beings.”

To find out, UChicago researchers—working with investigators at the University of California San Francisco, University of New Mexico, University of Pennsylvania, and the Angioma Alliance patient support group—collected stool samples from more than 120 CA patients.

The samples were then analyzed for their bacterial content and compared with samples from the general population. The CA samples showed significantly higher amounts of gram-negative bacteria and less gram-positive bacteria. The researchers identified a combination of three common bacterial species, whose relative abundance can distinguish CA patients from control patients without CA lesions, with high sensitivity and specificity.

The CA samples also showed an imbalanced network of bacteria that was much more disordered than the general population’s bacterial network. “The CA patients from all the different collection sites had the same distinctive microbiome, regardless of whether they had inherited the mutation or had a sporadic lesion, and regardless of the number of lesions they had,” Awad said. The investigators further showed that the bacterial imbalance in patients with CA produces lipopolysaccharide (LPS) molecules, which travel through the bloodstream to the brain and attach to the brain’s blood vessel lining, facilitating lesion development. “All this evidence pointed to the microbiome as a cause of lesions rather than an effect,” Awad said.

The investigators also collected blood from several CA patients and used advanced computational machine learning to identify the combination of molecular signals associated with the disease. Those with CA had significantly different LPS-related related blood biomarkers and inflammatory molecules. The result was essentially a smart, personalized test for each CA patient. “By looking at both bacteria combinations and the blood biomarkers, we were able to measure just how aggressive the disease was in each patient,” said Sean Polster, MD, a neurosurgery resident at UChicago Medicine and first author on the paper. Polster spent two years of his neurosurgery residency coordinating the study among the different institutions.

The researchers are beginning to think about how these results affect treatment. Earlier studies in mice showed that those fed emulsifiers—which are often used as preservatives in processed foods—had more bleeding in the brain, likely due to the way they disrupted the gut’s bacterial network. The researchers now tell patients to avoid these preservatives.

Though antibiotics and probiotics might seem like natural courses of treatment, they could change the bacterial balance in ways that lead to bigger problems. “This is more complicated than it appears,” said Awad. However, he tells CA patients who have infections caused by gram-negative bacteria (such as urinary tract infections or prostatitis) to have them treated right away to avoid more potential brain lesions.

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How does the brain link events to form a memory? Study reveals unexpected mental processes

A woman walking down the street hears a bang. Several moments later she discovers her boyfriend, who had been walking ahead of her, has been shot. A month later, the woman checks into the emergency room. The noises made by garbage trucks, she says, are causing panic attacks. Her brain had formed a deep, lasting connection between loud sounds and the devastating sight she witnessed.

This story, relayed by clinical psychiatrist and co-author of a new study Mohsin Ahmed, MD, Ph.D., is a powerful example of the brain’s powerful ability to remember and connect events separated in time. And now, in that new study in mice published today in Neuron, scientists at Columbia’s Zuckerman Institute have shed light on how the brain can form such enduring links.

The scientists uncovered a surprising mechanism by which the hippocampus, a brain region critical for memory, builds bridges across time: by firing off bursts of activity that seem random, but in fact make up a complex pattern that, over time, help the brain learn associations. By revealing the underlying circuitry behind associative learning, the findings lay the foundation for a better understanding of anxiety and trauma- and stressor-related disorders, such as panic and post-traumatic stress disorders, in which a seemingly neutral event can elicit a negative response.

“We know that the hippocampus is important in forms of learning that involve linking two events that happen even up to 10 to 30 seconds apart,” said Attila Losonczy, MD, Ph.D., a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper’s co-senior author. “This ability is a key to survival, but the mechanisms behind it have proven elusive. With today’s study in mice, we have mapped the complex calculations the brain undertakes in order to link distinct events that are separated in time.”

The hippocampus—a small, seahorse-shaped region buried deep in the brain—is an important headquarters for learning and memory. Previous experiments in mice showed that disruption to the hippocampus leaves the animals with trouble learning to associate two events separated by tens of seconds.

“The prevailing view has been that cells in the hippocampus keep up a level of persistent activity to associate such events,” said Dr. Ahmed, an assistant professor of clinical psychiatry at Columbia’s Vagelos College of Physicians and Surgeons, and co-first author of today’s study. “Turning these cells off would thus disrupt learning.”

To test this traditional view, the researchers imaged parts of the hippocampus of mice as the animals were exposed to two different stimuli: a neutral sound followed by a small but unpleasant puff of air. A fifteen-second delay separated the two events. The scientists repeated this experiment across several trials. Over time, the mice learned to associate the tone with the soon-to-follow puff of air. Using advanced two-photon microscopy and functional calcium imaging, they recorded the activity of thousands of neurons, a type of brain cell, in the animals’ hippocampus simultaneously over the course of each trial for many days.

“With this approach, we could mimic, albeit in a simpler way, the process our own brains undergo when we learn to connect two events,” said Dr. Losonczy, who is also a professor of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons.

To make sense of the information they collected, the researchers teamed up with computational neuroscientists who develop powerful mathematical tools to analyze vast amounts of experimental data.

“We expected to see repetitive, continuous neural activity that persisted during the fifteen-second gap, an indication of the hippocampus at work linking the auditory tone and the air puff,” said computational neuroscientist Stefano Fusi, Ph.D., a principal investigator at Columbia’s Zuckerman Institute and the paper’s co-senior author. “But when we began to analyze the data, we saw no such activity.”

Instead, the neural activity recorded during the fifteen-second time gap was sparse. Only a small number of neurons fired, and they did so seemingly at random. This sporadic activity looked distinctly different from the continuous activity that the brain displays during other learning and memory tasks, like memorizing a phone number.

“The activity appears to come in fits and bursts at intermittent and random time periods throughout the task,” said James Priestley, a doctoral candidate co-mentored by Drs. Losonczy and Fusi at Columbia’s Zuckerman Institute and the paper’s co-first author. “To understand activity, we had to shift the way we analyzed data and use tools designed to make sense of random processes.”

Ultimately, the researchers discovered a pattern in the randomness: a style of mental computing that seems to be a remarkably efficient way that neurons store information. Instead of communicating with each other constantly, the neurons save energy—perhaps by encoding information in the connections between cells, called synapses, rather than through the electrical activity of the cells.

“We were happy to see that the brain doesn’t maintain ongoing activity over all these seconds because, metabolically, that’s not the most efficient way to store information,” said Dr. Fusi, who is also a professor of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons. “The brain seems to have a more efficient way to build this bridge, which we suspect may involve changing the strength of the synapses.”

In addition to helping to map the circuitry involved in associative learning, these findings also provide a starting point to more deeply explore disorders involving dysfunctions in associative memory, such as panic and pos-ttraumatic stress disorder.

“While our study does not explicitly model the clinical syndromes of either of these disorders, it can be immensely informative,” said Dr. Ahmed, who is also a member of the Losonczy lab at Columbia’s Zuckerman Institute. “For example, it can help us to model some aspects of what may be happening in the brain when patients experience a fearful association between two events that would, to someone else, not elicit fright or panic.”

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