Decoding the complexity of Alzheimer's disease

 Alzheimer's disease affects more than 6 million people in the United States, and there are very few FDA-approved treatments that can slow the progression of the disease.

In hopes of discovering new targets for potential Alzheimer's treatments, MIT researchers have performed the broadest analysis yet of the genomic, epigenomic, and transcriptomic changes that occur in every cell type in the brains of Alzheimer's patients.

Using more than 2 million cells from more than 400 postmortem brain samples, the researchers analyzed how gene expression is disrupted as Alzheimer's progresses. They also tracked changes in cells' epigenomic modifications, which help to determine which genes are turned on or off in a particular cell. Together, these approaches offer the most detailed picture yet of the genetic and molecular underpinnings of Alzheimer's.

The researchers report their findings in a set of four papers appearing today in Cell. The studies were led by Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory, and Manolis Kellis, a professor of computer science in MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard.

"What we set out to do was blend together our computational and our biological expertise and take an unbiased look at Alzheimer's at an unprecedented scale across hundreds of individuals -- something that has just never been undertaken before," Kellis says.

The findings suggest that an interplay of genetic and epigenetic changes feed on each other to drive the pathological manifestations of the disease.

"It's a multifactorial process," Tsai says. "These papers together use different approaches that point to a converging picture of Alzheimer's disease where the affected neurons have defects in their 3D genome, and that is causal to a lot of the disease phenotypes we see."

A complex interplay

Many efforts to develop drugs for Alzheimer's disease have focused on the amyloid plaques that develop in patients' brains. In their new set of studies, the MIT team sought to uncover other possible approaches by analyzing the molecular drivers of the disease, the cell types that are the most vulnerable, and the underlying biological pathways that drive neurodegeneration.

To that end, the researchers performed transcriptomic and epigenomic analyses on 427 brain samples from the Religious Orders Study/Memory and Aging Project (ROSMAP), a longitudinal study that has tracked memory, motor, and other age-related changes in older people since 1994. These samples included 146 people with no cognitive impairment, 102 with mild cognitive impairment, and 144 diagnosed with Alzheimer's-linked dementia.

In the first Cell paper, focused on gene expression changes, the researchers used single-cell RNA-sequencing to analyze the gene expression patterns of 54 types of brain cells from these samples, and identified cellular functions that were most affected in Alzheimer's patients. Among the most prominent, they found impairments in the expression of genes involved in mitochondrial function, synaptic signaling, and protein complexes needed to maintain the structural integrity of the genome.

Source: ScienceDaily

Plant chloroplasts promise potential therapy for Huntington's disease

 Researchers at the University of Cologne's CECAD Cluster of Excellence for Aging Research and the CEPLAS Cluster of Excellence for Plant Sciences have found a promising synthetic plant biology approach for the development of a therapy to treat human neurodegenerative diseases, especially Huntington's disease. In their publication "In-planta expression of human polyQ-expanded huntingtin fragment reveals mechanisms to prevent disease-related protein aggregation" in Nature Aging, they showed that a synthetic enzyme derived from plants -- stromal processing peptidase (SPP) -- reduces the clumping of proteins responsible for the pathological changes in models of Huntington's disease in human cells and the nematode Caenorhabditis elegans.

Huntington's disease is among the so called polyglutamine (polyQ) diseases, a group of neurodegenerative disorders caused by multiple repetitions of glutamine amino acids in specific proteins. An excessive number of polyQ repeats can cause proteins to aggregate or accumulate in harmful and damaging protein deposits, leading to cellular dysfunction and death. To date, nine polyQ disorders have been described in humans. They all remain incurable. Among them, Huntington's disease is an inherited condition that causes widespread deterioration in the brain and disrupts thinking, behavior, emotion and movement.

Plants are immune to harmful protein aggregation

In their recent study, Professor Dr David Vilchez (CECAD) and Dr Ernesto Llamas (CEPLAS) followed an unconventional approach to find potential drugs to treat polyQ diseases like Huntington's. Plants are constantly challenged by the environment, but they cannot move to escape from these conditions. However, plants possess a striking resilience to stress that allows them to live long. Unlike humans who suffer from proteinopathies caused by the toxic aggregation or cluster of proteins, plants do not experience these kinds of diseases. They express hundreds of proteins containing polyQ repeats, but no pathologies from these factors have been reported. To explore how plants deal with toxic protein aggregation, Dr Ernesto Llamas, first author of the study, and colleagues introduced the toxic mutant protein huntingtin in plants, which causes cell death in human neurons. In contrast to animal and human models, they found that Arabidopsis thaliana plants actively removed huntingtin protein clumps and avoid harmful effects.

By means of synthetic biology, the scientists then transferred the plants' ability to avoid aggregation into human cultivated cells and animal models of Huntington's disease. Their hope is that the use of plant proteins could lead to new therapeutic approaches for treating Huntington's disease and other neurodegenerative diseases.

"We were surprised to see plants completely healthy, even though they were genetically producing the toxic human protein. The expression of mutant huntingtin in other models of research like human cultured cells, mice and nematode worms induce detrimental effects and symptoms of disease," said David Vilchez.

Plant protein alleviates symptoms in human cells and nematodes

The next step was to discover how plants avoided the toxic aggregation of mutant huntingtin. Indeed, the scientists discovered that the chloroplasts, the plant-specific organelles that perform photosynthesis, were the reason why plants do not show toxic protein deposits. Llamas said: "Unlike humans, plants have chloroplasts, an extra cellular type of organelle that could provide an expanded molecular machinery to get rid of toxic protein aggregates."

Source: ScienceDaily

Advanced bladder cancer patients could keep their bladder under new treatment regime, clinical trial shows

 Mount Sinai investigators have developed a new approach for treating invasive bladder cancer without the need for surgical removal of the bladder, according to a study published in Nature Medicine in September. Removing the bladder is currently a standard approach when cancer has invaded the muscle layer of the bladder.

In a phase 2 clinical trial that was the first of its kind, doctors found that some patients could be treated with a combination of chemotherapy and immunotherapy without the need to remove their bladder. Surgical removal of the bladder can be curative in muscle-invasive bladder cancer, but the procedure can have profound effects on a patient's quality of life.

"Treatment for muscle-invasive bladder cancer is in need of major improvements from both a quality-of-life and an effectiveness standpoint," said Matthew Galsky, MD, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute, a part of the Tisch Cancer Center at Mount Sinai. "If additional research confirms our findings, this may lead to a new paradigm in the treatment of muscle-invasive bladder cancer."

Seventy-six patients participated in this clinical trial, and approximately 43 percent achieved a complete response -- no detectable cancer -- when treated with the combination of chemotherapy and immunotherapy. Patients with a clinical complete response were offered the opportunity to proceed with additional immunotherapy, without surgical removal of the bladder. Among patients opting to proceed without surgical removal of the bladder, about 70 percent had no evidence of recurrent cancer after two years. Based on the results of this trial, two follow-up studies were launched to build on this approach; one is ongoing, and another will open in the next six months.

Colleagues at City of Hope, the University of Pennsylvania, the University of Wisconsin, the University of Southern California, the University of Utah, and Oregon Health and Sciences University also participated in this research. This study was funded by Bristol Myers-Squibb, the Foundation for the NIH/Partnership for Accelerating Cancer Therapies, and the V Foundation.

Source: ScienceDaily

Study indicates possible link between chronic stress and Alzheimer's disease

 Researchers from Karolinska Institutet have published a study in Alzheimer's Research & Therapy that addresses possible associations between chronic stress, mild cognitive impairment and Alzheimer's disease. The study shows how people aged between 18 and 65 with a previous diagnosis of chronic stress and depression were more likely than other people to be diagnosed with mild cognitive impairment or Alzheimer's disease.

Some 160,000 people have some form of dementia in Sweden, Alzheimer's disease being the most common, a figure that is rising with our life expectancy. At the same time, many new diagnostic methods and early-intervention therapies have been developed in recent years, which foregrounds the need to identify more risk factors for the disease.

Previous studies have demonstrated a possible association between chronic stress, depression and dementia. This present study now shows that people who have been diagnosed with chronic stress or depression are more likely to be diagnosed with Alzheimer's disease.

The study shows that the risk of Alzheimer's disease was more than twice as high in patients with chronic stress and in patients with depression as it was in patients without either condition; in patients with both chronic stress and depression it was up to four times as high.

The risk of developing cognitive impairment was elevated about as much. A patient is deemed to be suffering chronic stress when he or she has been under stress with no opportunity for recuperation for at least six months.

"The risk is still very small and the causality is unknown," says the study's last author Axel C. Carlsson, docent at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet. "That said, the finding is important in that it enables us to improve preventative efforts and understand links with the other risk factors for dementia."

The study was conducted using Region Stockholm's administrative healthcare database, which contains all healthcare contacts compensated by the region. The researchers focused on patients between the ages of 18 and 65 and between 2012 and 2013. They identified 44,447 people with a diagnosis of chronic stress and/or depression and followed them for eight years to see how many of them were later diagnosed with mild cognitive impairment or Alzheimer's disease.

A comparison with all other 1,362,548 individuals in the age bracket showed that more people with chronic stress or depression had also been diagnosed with mild cognitive impairment or Alzheimer's disease.

"It's very uncommon for people in this age group to develop dementia, so we need to identify all possible risk factors for the disease," says Dr Carlsson. "We show here that the diagnosis is more common in people who have suffered chronic stress or depression, but more studies will be required if we're to demonstrate any causality there."

The researchers will now be continuing their work and developing questionnaires and cognitive tests to aid the early identification of people at risk of dementia.

The study was financed by Region Stockholm and conducted with the Academic Primary Care Centre (APC).

Source: ScienceDaily

Origin of cultural learning: Babies imitate because they are imitated

 People are constantly learning from others without even being aware of it. Social learning avoids laborious trial and error; the wheel does not have to be reinvented each time. But where does this ability come from, which forms the basis of cultural learning and consequently for the evolutionary success of the human species?

A study led by Professor Markus Paulus, Chair of Developmental Psychology and Educational Psychology at LMU, demonstrates that the ability has its roots in earliest childhood. "Children acquire their ability to imitate because they themselves are imitated by their caregivers," says Markus Paulus.

Children are incredible imitators -- thanks to their parents

For the study, the researchers looked at the interaction between mother and child over several months. The babies came into the lab for the first time at the age of 6 months, while their final visit was when they were 18 months old. As they engaged in various play situations, the interactions and imitations of mother and child were analyzed.

The longitudinal study shows that the more sensitive a mother was in her interactions with her six-month-old child and the more often she imitated the infant, the greater the child's ability was at the age of 18 months to imitate others.

In the interaction between parents and child, mutual imitation is a sign of communication. Parents respond to the signals given by the child and reflect and amplify them. A mutual imitation of actions and gestures develops. "These experiences create connections between what the child feels and does on the one hand and what it sees on the other. Associations are formed. The child's visual experience is connected to its own motor activity," says Markus Paulus, explaining the neuro-cognitive process.

Children learn a variety of skills through imitation, such as how to use objects, cultural gestures like waving, and the acquisition of language. "Children are incredible imitators. Mimicry paves the way to their further development. Imitation is the start of the cultural process toward becoming human," says Markus Paulus. In psychology, the theory that the ability to imitate is inborn held sway for a long time. The LMU study is further evidence that the ability is actually acquired.

The cultural transfer of knowledge is based on imitation

How well children learn to imitate others is crucially dependent on the sensitivity with which their parents respond to them. In this context, sensitivity is defined as the capability of a caregiver to pick up on the child's signals and react promptly and appropriately to them. "The sensitivity of the mother is a predictor of how strongly she imitates her child," says Dr. Samuel Essler, lead author of the study.

In addition, the study sheds light on what makes humans social beings, namely that our individual abilities only develop through interaction with others. Indeed, they owe their existence to the particular way in which humans raise their young.

"By being part of a social interaction culture, in which they are imitated, children learn to learn from others. Over the course of generations and millennia, this interplay has led to the cultural evolution of humans," says Markus Paulus. "Through social learning, certain actions or techniques do not have to be constantly invented anew, but there is a cultural transfer of knowledge. Our results show that the ability to imitate, and thus cultural learning, is itself a product of cultural learning, in particular the parent-child interaction."

Source: ScienceDaily

New study provides evidence for more effective brain-based treatment of chronic back pain

 A new study in JAMA Network Open may provide key answers to how to help people experiencing chronic back pain.

The study, published today, examined the critical connection between the brain and pain for treating chronic pain. Specifically, they looked at the importance of pain attributions, which are people's beliefs about the underlying causes of their pain, to reduce chronic back pain severity.

"Millions of people are experiencing chronic pain and many haven't found ways to help with the pain, making it clear that something is missing in the way we're diagnosing and treating people," said the study's first author Yoni Ashar, PhD, assistant professor of internal medicine at the University of Colorado Anschutz Medical Campus.

Ashar and his team tested whether the reattribution of pain to mind or brain processes was associated with pain relief in pain reprocessing therapy (PRT), which teaches people to perceive pain signals sent to the brain as less threatening. Their goal was to better understand how people recovered from chronic back pain. The study revealed after PRT, patients reported reduced back pain intensity.

"Our study shows that discussing pain attributions with patients and helping them understand that pain is often 'in the brain' can help reduce it," Ashar said.

To study the effects of pain attributions, they enrolled over 150 adults experiencing moderately severe chronic back pain in a randomized trial to receive PRT. They found two-thirds of people treated with PRT reported being pain-free or nearly so after treatment, compared to only 20% of placebo controls.

"This study is critically important because patients' pain attributions are often inaccurate. We found that very few people believed their brains had anything to do with their pain. This can be unhelpful and hurtful when it comes to planning for recovery since pain attributions guide major treatment decisions, such as whether to get surgery or psychological treatment," said Ashar.

Before PRT treatment, only 10% of participants' attributions of PRT treatment were mind- or brain-related. However, after PRT, this increased to 51%. The study revealed that the more participants shifted to viewing their pain as due to mind or brain processes, the greater the reduction in chronic back pain intensity they reported.

"These results show that shifting perspectives about the brain's role in chronic pain can allow patients to experience better results and outcomes," Ashar adds.

Ashar says that one reason for this may be that when patients understand their pain as due to brain processes, they learn that there is nothing wrong with their body and that the pain is a 'false alarm' being generated by the brain that they don't need to be afraid of.

The researchers hope this study will encourage providers to talk to their patients about the reasons behind their pain and discuss causes outside of biomedical ones.

"Often, discussions with patients focus on biomedical causes of pain. The role of the brain is rarely discussed," said Ashar. "With this research, we want to provide patients as much relief as possible by exploring different treatments, including ones that address the brain drivers of chronic pain."

Source: ScienceDaily

Calls for verbal abuse of children by adults to be formally recognized as form of child maltreatment

 A new systematic review by researchers at UCL and Wingate University has highlighted the importance of identifying childhood verbal abuse by adults as a standalone subtype of child maltreatment, to ensure targeted prevention and address the lasting harm it can inflict.

Child maltreatment is currently classified into four subtypes: physical abuse, sexual abuse, emotional abuse, and neglect. These classifications guide the creation of interventions and the monitoring of affected populations.

The study, published in Child Abuse & Neglect: The International Journal and commissioned by charity, Words Matter, examines a total of 149 quantitative and 17 qualitative studies to assess how child verbal abuse is currently defined and measured.

Researchers found that there needs to be a more consistent way of defining childhood verbal abuse, as it currently varies between parents and other authorities, with it being normalised in some cultures as a form of discipline.

The nature of childhood verbal abuse involves behaviours that can be detrimental to a child's wellbeing, such as belittling, shouting, and threatening language.

It was found that these actions could have a lasting impact throughout the child's life, creating underlying emotional and psychological repercussions, including increased risks of anger, depression, substance abuse, self-harm and obesity.

However, the team noted that there was a noticeable void in acknowledging childhood verbal abuse by adults as a distinct maltreatment subtype and that doing so would be a starting point for its identification and prevention.

Co-author, Professor Peter Fonagy (UCL Psychology & Language Sciences), said: "This systematic review is timely and of significant clinical value. Preventing the maltreatment of children is the most effective way we can reduce the prevalence of child metal health problems. A sharp focus on childhood verbal abuse by adults around them by the new charity Words Matter, and this review will help make significant change, and support and direct our efforts to identify and respond to this risk in an effective and timely manner."

Data from the World Health Organization (WHO) has found that emotional abuse is now the most prevalent form of child maltreatment, ahead of physical or sexual abuse.

However, researchers found that the term "emotional abuse" was ambiguous and focused on the victim.

Whereas the term "childhood verbal abuse" zeroes in on the adult's actions and this onus could be a starting point for prevention, were it to be made a subtype in its own right.

There was also a range of varying terminology associated with "verbal abuse" across the studies, with terms such as "verbal aggression," "verbal hostility" and "verbal abuse" being used -- highlighting the need for standardised terminology in this area.

Source: ScienceDaily