Mystery solved: New study reveals how DNA repair genes play a major role in Huntington's disease

Dr. Xiangdong William Yang
Photo Credit: Courtesy of UCLA/Health

A new UCLA Health study has discovered in mouse models that genes associated with repairing mismatched DNA are critical in eliciting damages to neurons that are most vulnerable in Huntington's disease and triggering downstream pathologies and motor impairment, shedding light on disease mechanisms and potential new ways to develop therapies. 

Huntington’s disease is one of the most common inherited neurodegenerative disorders that typically begins in adulthood and worsens over time. Patients begin to lose neurons in specific regions of the brain responsible for movement control, motor skill learning, language and cognitive function. Patients typically live 15 to 20 years after diagnosis with symptoms worsening over time. There is no known cure or therapy that alters the course of the disease.

The cause of Huntington's disease was discovered over three decades ago--a "genetic stutter" mutation involves repeats of three letters of the DNA, cytosine-adenine-guanine (CAG), in a gene called huntingtin. Healthy individuals usually have 35 or fewer CAG repeats, but people inherited with mutation of 40 or more repeats will develop the disease. The more CAG repeats a person inherits, the earlier the disease onset occurs. However, how the mutation causes the disease remains poorly understood. 

Study reveals reasons for misdiagnosis of frontotemporal dementia

Researchers have discovered patterns in the misdiagnosis of frontotemporal dementia
Photo Credit: Anna Shvets

University of Queensland researchers discovered that nearly 70 per cent of suspected frontotemporal dementia patients ultimately did not have the disease, in a study aimed at identifying factors that contribute to misdiagnosis of this notoriously difficult to diagnose disorder.

Psychiatrist Dr Joshua Flavell, working with cognitive neurologist Professor Peter Nestor at the Mater Hospital Memory and Cognitive Disorders clinic and UQ’s Queensland Brain Institute, analyzed data from 100 patients suspected of having frontotemporal dementia who had been referred by specialist physicians like neurologists, psychiatrists or geriatricians.

“Of the 100 patients, 34 were true-positive, and 66 were false-positive for frontotemporal dementia,” Dr Flavell said.

“We found that misinterpretation of brain scans, particularly nuclear imaging, led to 32 patients being incorrectly diagnosed.

What drives mood swings in bipolar disorder? Study points to a second brain clock

Image Credit: Scientific Frontline

A brain rhythm working in tandem with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression, according to new research.

The McGill University-led study published in Science Advances marks a breakthrough in understanding what drives shifts between the two states, something that, according to lead author Kai-Florian Storch, is considered the “holy grail” of bipolar-disorder research.

“Our model offers the first universal mechanism for mood switching or cycling, which operates analogously to the sun and the moon driving spring tides at specific, recurring times,” said Storch, an Associate Professor in McGill’s Department of Psychiatry and a researcher at the Douglas Research Centre.

The findings suggest that regularly occurring mood switches in bipolar disorder patients are controlled by two “clocks”: the biological 24-hour clock, and a second clock that is driven by dopamine-producing neurons that typically influence alertness. A manic or depressed state may arise depending on how these two clocks, which run at different speeds, align at a given time.

Researchers detect that people with schizophrenia have an altered ability to visually perceive contrast

UB researchers Cristina de la Malla and Daniel Linares.
Photo Credit: Courtesy of University of Barcelona

According to a review of more than 600 studies, these patients would have difficulty in detecting differences in light intensity between adjacent areas, without which they cannot adequately see their surroundings and objects.

The article, published in the journal Schizophrenia Bulletin, is signed by researchers Daniel Linares and Cristina de la Malla, together with master’s student Aster Joostens, from the Vision and Control of Action Group of the Faculty of Psychology and the UB Institute of Neurosciences (UBneuro).

A key indicator of visual function

The symptoms of schizophrenia are characterized by alterations in thinking and behavior, such as loss of contact with reality, delusions or hallucinations, but there are also abnormalities in the perception of visual stimuli, such as deficits in the perception of color or contrast. Understanding these abnormalities may provide clues as to how information processing disturbances contribute to the characteristic symptoms of schizophrenia. “Contrast perception is one of the most fundamental abilities of vision, as without it, we cannot adequately perceive the environment and the objects in it, which can compromise everyday tasks such as moving through space, recognizing faces or reading”, explains the research team, part of the Department of Cognition, ​​​​​​​Development and Educational Psychology.

Drawing a Line from the Gut Microbiome to Inflammation and Depression

Morganella morganii bacteria on a plate.
Photo Credit: Ajay Kumar Chaurasiya
(CC BY-SA 4.0)

It’s become increasingly clear that the gut microbiome can affect human health, including mental health. Which bacterial species influence the development of disease and how they do so, however, is only just starting to be unraveled.

For instance, some studies have found compelling links between one species of gut bacteria, Morganella morganii, and major depressive disorder. But until now no one could tell whether this bacterium somehow helps drive the disorder, the disorder alters the microbiome, or something else is at play.

Harvard Medical School researchers have now pinpointed a biologic mechanism that strengthens the evidence that M. morganii influences brain health and provides a plausible explanation for how it does so.

The findings, published in the Journal of the American Chemical Society, implicate an inflammation-stimulating molecule and offer a new target that could be useful for diagnosing or treating certain cases of the disorder. They also provide a roadmap for probing how other members of the gut microbiome influence human health and behavior.

“There is a story out there linking the gut microbiome with depression, and this study takes it one step further, toward a real understanding of the molecular mechanisms behind the link,” said senior author Jon Clardy, the Christopher T. Walsh, PhD Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at HMS.

Eight Psychiatric Disorders Share the Same Genetic Causes

Image Credit: Won Lab

Building off previous groundbreaking research, a new study identifies specific genetic variants that have significant impacts on brain development and are shared across eight different psychiatric disorders. Targeting these variants could pave the way for treatments that address multiple conditions at once.

Psychiatric disorders often overlap and can make diagnosis difficult. Depression and anxiety, for example, can coexist and share symptoms. Schizophrenia and anorexia nervosa. Autism and attention deficit/hyperactivity disorder, too. But, why?

Life experiences, environment, and genetics can all influence psychiatric disorders, but much of it comes down to variations in our genetics. Over the past few years, scientists in the field of psychiatric genetics have found that there are common genetic threads that may be linking and causing coexisting psychiatric disorders.

In 2019, researchers at the Psychiatric Genomics Consortium, Harvard University, and the UNC School of Medicine identified 136 “hot spots” within the genome that are associated with eight psychiatric disorders. Among them, 109 hot spots were shared among multiple disorders, or “pleiotropic”. However, it was not clear at the time how genetic variations within these hot spots differed from those that only have roles in only one disorder.

Feeding the lonely brain

Study finds that lonely women experienced increased activation in regions of the brain associated with food cravings
Photo Credit: Ryanwar Hanif

A new UCLA Health study has found that women who perceive themselves to be lonely exhibited activity in regions of the brain associated with cravings and motivation towards eating especially when shown pictures of high calorie foods such as sugary foods. The same group of women also had unhealthy eating behaviors and poor mental health.

Arpana Gupta, Ph.D., a researcher and co-director of the UCLA Goodman-Luskin Microbiome Center, wanted to research the negative impacts of loneliness, especially as people continue to be working remotely after the COVID-19 pandemic, and how the brain interplays with social isolation, eating habits, and mental health. While it is established that obesity is linked to depression and anxiety, and that binge eating is understood to be a coping mechanism against loneliness, Gupta wanted to observe the brain pathways associated with these feelings and behaviors.

“Researching how the brain processes loneliness and how this is related to obesity and health outcomes hasn't been done,” said Gupta, senior author of the paper, which is published in JAMA Network Open. 

The researchers surveyed 93 women about their support system and their feelings of loneliness and isolation, then separated them into two groups: those who scored high on the perceived social isolation scale, and those who scored low. The researchers found that women who had higher levels of social isolation tended to have higher fat mass, lower diet quality, greater cravings, reward-based eating, and uncontrolled eating, and increased levels of anxiety and depression.

Autism and ADHD are linked to disturbed gut flora very early in life

The researchers have found links between the gut flora in babies first year of life and future diagnoses.
Photo Credit: Cheryl Holt

Disturbed gut flora during the first years of life is associated with diagnoses such as autism and ADHD later in life. This is according to a study led by researchers at the University of Florida and Linköping University and published in the journal Cell.

The study is the first forward-looking, or prospective, study to examine gut flora composition and a large variety of other factors in infants, in relation to the development of the children's nervous system. The researchers have found many biological markers that seem to be associated with future neurological development disorders, such as autism spectrum disorder, ADHD, communication disorder and intellectual disability.

“The remarkable aspect of the work is that these biomarkers are found at birth in cord blood or in the child’s stool at one year of age over a decade prior to the diagnosis,” says Eric W Triplett, professor at the Department of Microbiology and Cell Science at the University of Florida, USA, one of the researchers who led the study.

Ultrasound therapy shows promise as a treatment for Alzheimer’s disease

Professor Jürgen Götz with an ultrasound machine.
Photo Credit: Courtesy of University of Queensland

University of Queensland researchers have found targeting amyloid plaque in the brain is not essential for ultrasound to deliver cognitive improvement in neurodegenerative disorders.

Dr Gerhard Leinenga and Professor Jürgen Götz from UQ’s Queensland Brain Institute (QBI) said the finding challenges the conventional notion in Alzheimer’s disease research that targeting and clearing amyloid plaque is essential to improve cognition.

“Amyloid plaques are clumps of protein that can build up in the brain and block communication between brain cells, leading to memory loss and other symptoms of Alzheimer’s disease,” Dr Leinenga said.

“Previous studies have focused on opening the blood-brain barrier with microbubbles, which activate the cell type in the brain called microglia which clears the amyloid plaque. 

“But we used scanning ultrasound alone on mouse models and observed significant memory enhancement.”

Pilot study shows ketogenic diet improves severe mental illness

A study led by researchers at Stanford Medicine showed that diet can help those with serious mental illness.

Video Credit: Stanford Medicine

For people living with serious mental illness like schizophrenia or bipolar disorder, standard treatment with antipsychotic medications can be a double-edged sword. While these drugs help regulate brain chemistry, they often cause metabolic side effects such as insulin resistance and obesity, which are distressing enough that many patients stop taking the medications.

Now, a pilot study led by Stanford Medicine researchers has found that a ketogenic diet not only restores metabolic health in these patients as they continue their medications, but it further improves their psychiatric conditions. The results published in Psychiatry Research, suggest that a dietary intervention can be a powerful aid in treating mental illness.

“It’s very promising and very encouraging that you can take back control of your illness in some way, aside from the usual standard of care,” said Shebani Sethi, MD, associate professor of psychiatry and behavioral sciences and the first author of the new paper.

The aging brain: protein mapping furnishes new insights

Stained mouse microvessels under the fluorescence microscope (green: vascular endothelium, red: cell nuclei). 
Image Credit: © Dichgans Lab

For the neurons in the brain to work smoothly and be able to process information, the central nervous system needs a strictly regulated environment. This is maintained by the blood-brain barrier, whereby specialized brain endothelial cells lining the inner walls of blood vessels regulate the exchange of molecules between the circulatory and nervous systems. Earlier studies have shown that various functions that are dependent on these cells, such as the integrity of the blood-brain barrier or the regulation of blood supply to the brain, decline over the course of a person’s life. This dysregulation leads to a dysfunction of the brain vasculature and is therefore a major contributor to medical conditions such as strokes and dementia.

However, the molecular changes that underlie this loss of function have remained largely obscure. To improve our mechanistic understanding, researchers carry out molecular profiling studies to investigate the different components of brain endothelial cells and collect their findings in large databases. “The transcriptome – that is to say, the RNA contained in endothelial cells – has since been quite comprehensively mapped,” says LMU professor Martin Dichgans, Director of the Institute for Stroke and Dementia Research at University of Munich Hospital and Principal Investigator at the SyNergy Cluster of Excellence. “What has been lacking is corresponding data on the complete set of proteins in the cells, the proteome.” A study recently published in the journal Nature Aging, which had major contributions by researchers from LMU and SyNergy, has now closed this knowledge gap.

Dopamine production is not behind vulnerability to cocaine abuse

Averaged parametric brain maps of [18F]-FDOPA kicer, and index of dopamine synthesis capacity, in high- and low-impulsive rats before and after repeated cocaine self-administration.
Image Credit: © 2024 Urueña-Méndez et al.

Why do some people who try drugs struggle with substance abuse while others don’t? This question has long puzzled scientists. A team from the University of Geneva (UNIGE) explored the complex interplay between personality traits and brain chemistry. The scientists studied the role of impulsivity and the production of dopamine – the so-called "happiness hormone" – in influencing the risk of cocaine abuse. These results, published in eNeuro, offer new keys to understanding vulnerability to drug abuse, which could lead to the development of more targeted interventions for people at risk.

When a person consumes an addictive drug, his or her dopamine release surges, creating a “high” feeling. With repeated drug use, this dopamine release drops, potentially driving the person to increase drug consumption. This mechanism varies between individuals, with some showing a greater propensity to consume the drug while others don’t. However, the reasons for these differences are unknown.

Gut-brain communication turned on its axis

How the gut communicates with the brain
Image Credit: Copilot AI

The mechanisms by which antidepressants and other emotion-focused medications work could be reconsidered due to an important new breakthrough in the understanding of how the gut communicates with the brain.

New research led by Flinders University has uncovered major developments in understanding how the gut communicates with the brain, which could have a profound impact on the make-up and use of medications such as antidepressants.

“The gut-brain axis consists of complex bidirectional neural communication pathway between the brain and the gut, which links emotional and cognitive centers of the brain,” says Professor Nick Spencer from the College of Medicine and Public Health.

“As part of the gut-brain axis, vagal sensory nerves relay a variety of signals from the gut to the brain that play an important role in mental health and wellbeing.

“The mechanisms by which vagal sensory nerve endings in the gut wall are activated has been a major mystery but remains of great interest to medical science and potential treatments for mental health and wellbeing.”

Sleep improves ability to recall complex events

Sleep is important for reinforcing complex associations, the basis for completing memories of entire events
Photo Credit: Shane

Researchers have known for some time that sleep consolidates our memories of facts and episodic events. However, the research to date has concentrated mainly on simple associations – that is to say, connections between elements, such as we make when learning new vocabulary. “But in real life, events are generally made up of numerous components – for example, a place, people, and objects – which are linked together in the brain,” explains Dr. Nicolas Lutz from LMU’s Institute of Medical Psychology. These associations can vary in strength and some elements might be connected with each other only indirectly. “Thanks to the neural connections that underlie these associations, a single cue word is often all it takes for somebody to recall not only individual aspects of an event but multiple aspects at once.” This process, which is known as pattern completion, is a fundamental feature of episodic memory. Lutz is lead author of a study recently published in the journal Proceedings of the National Academy of Sciences (PNAS), which investigated the effect of sleep on memory of such complex events.

Oregon State study sheds light on links between cognitive and motor skill development in children with autism

Image Credit: Aedrian

A recent study by Oregon State University researchers highlighted the ways motor skills and cognitive skills develop in connection with each other in young children with autism, and found an opportunity for behavioral and physical therapists to work together to improve care.

“We know they’re highly linked, but we often talk about them in different domains,” said study co-author Megan MacDonald, head of the School of Exercise, Sport, and Health Science in OSU’s College of Health. “When we look at wraparound services and talk about academic, social, physical and cognitive services, there’s so much we could do together.”

When assessing, diagnosing and providing services for young children with autism, providers are often siloed from each other, MacDonald said. Occupational and physical therapists focus on fine and gross motor skills, while behavioral therapists focus on emotional regulation and executive function.

But in many situations, the two sides depend on each other, she said. Fine motor skills are closely linked to cognition, such as the combination of moves kids must remember and perform in the correct order to write their name. The gross motor skills used in a playground game of kickball work in tandem with the social and emotional skills used to interact with other students and work as a team.

Study finds childhood bullying linked to distrust and mental health problems in adolescence

Photo Credit: Mikhail Nilov

A new study, co-led by UCLA Health and the University of Glasgow, found that young teenagers who develop a strong distrust of other people as a result of childhood bullying are substantially more likely to have significant mental health problems as they enter adulthood compared to those who do not develop interpersonal trust issues.

The study, published in the journal Nature Mental Health on Feb. 13, is believed to be the first to examine the link between peer bullying, interpersonal distrust, and the subsequent development of mental health problems, such as anxiety, depression, hyperactivity and anger. 

Researchers used data from 10,000 children in the United Kingdom who were studied for nearly two decades as part of the Millennium Cohort Study. From these data, the researchers found that adolescents who were bullied at age 11 and in turn developed greater interpersonal distrust by age 14 were around 3.5 times more likely to experience clinically significant mental health problems at age 17 compared to those who developed less distrust.

Researchers identify brain hub with key role in learned response to direct and indirect threats

Diagram of mouse prefrontal cortex showing neural projections to the midbrain (purple) and the amygdala (green), pathways involved in learning about threat.
Image Credit: National Institute on Alcohol Abuse and Alcoholism

NIH-supported study in mice could inform treatments of trauma- and stress-related psychiatric conditions.

Scientists have identified an area within the brain’s frontal cortex that may coordinate an animal’s response to potentially traumatic situations. Understanding where and how neural circuits involving the frontal cortex regulate such functions, and how such circuits could malfunction, may provide insight about their role in trauma-related and stress-related psychiatric disorders in people. The study, led by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), a part of the National Institutes of Health, was published in Nature.

“Experiencing traumatic events is often at the root of trauma-related and stress-related psychiatric conditions, including alcohol use disorder (AUD),” said the study’s senior author, Andrew Holmes, Ph.D., senior investigator in NIAAA’s Laboratory of Behavioral and Genomic Neuroscience. “Additionally, witnessing others experience traumatic events can also contribute to these disorders.”

Enlarged Spaces in Infant Brains Linked to Higher Risk of Autism, Sleep Problems

Dea Garic, PhD, and Mark Shen, PhD, both in the UNC School of Medicine’s Department of Psychiatry, have found that enlarged perivascular spaces in the brains of babies, caused by an accumulation of excess cerebrospinal fluid, have a 2.2 times greater chance of developing autism later in life.
Photo Credit: Courtesy of University of North Carolina at Chapel Hill

Throughout the day and night, cerebrospinal fluid (CSF) pulses through small fluid-filled channels surrounding blood vessels in the brain, called perivascular spaces, to flush out neuroinflammation and other neurological waste. A disruption to this vital process can lead to neurological dysfunction, cognitive decline, or developmental delays.

For the first time, researchers Dea Garic, PhD, and Mark Shen, PhD, both at the UNC School of Medicine’s Department of Psychiatry, discovered that infants with abnormally enlarged perivascular spaces have a 2.2 times greater chance of developing autism compared to infants with the same genetic risk. Their research also indicated that enlarged perivascular spaces in infancy are associated with sleep problems seven to 10 years after diagnosis.

“These results suggest that perivascular spaces could serve as an early marker for autism,” said Garic, assistant professor of psychiatry and a member of the Carolina Institute for Developmental Disabilities (CIDD).

The researchers studied infants at increased likelihood for developing autism, because they had an older sibling with autism. They followed these infants from 6-24 months of age, before the age of autism diagnosis. Their study, published in JAMA Network Open, found that thirty percent of infants who later developed autism had enlarged perivascular spaces by 12 months. By 24 months of age, nearly half of the infants diagnosed with autism had enlarged perivascular spaces.

Brain health in over 50s deteriorated more rapidly during the pandemic

Photo Credit: Gabriel Porras

Brain health in over 50s deteriorated more rapidly during the pandemic, even if they didn’t have COVID-19, according to major new research linking the pandemic to sustained cognitive decline.

Researchers looked at results from computerized brain function tests from more than 3,000 participants of the online PROTECT study, who were aged between 50 and 90 and based in the UK. The remote study, led by teams at the University of Exeter and the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, and part-funded by NIHR Maudsley BRC, tested participants’ short-term memory and ability to complete complex tasks.

Through analyzing the results from this big dataset, researchers found that cognitive decline quickened significantly in the first year of the pandemic, when they found a 50 per cent change to the rate of decline across the study group. This figure was higher in those who already had mild cognitive decline before the pandemic, according to the research published in The Lancet Healthy Longevity.

High metabolism is an early sign of Alzheimer’s disease

Illustration Credit: geralt

An early phase in the process of developing Alzheimer’s disease is a metabolic increase in a part of the brain called the hippocampus, report researchers from Karolinska Institutet in a study published in Molecular Psychiatry. The discovery opens up new potential methods of early intervention.

Alzheimer’s disease is the most common form of dementia and strikes about 20,000 people in Sweden every year. Researchers now show that a metabolic increase in the mitochondria, the cellular power plants, is an early indicator of the disease. 

The teams behind the study used mice that developed Alzheimer’s disease pathology in a similar way to humans. The increase in metabolism in young mice was followed by synaptic changes caused by disruption to the cellular recycling system (a process known as autophagy), a finding that was awarded the Nobel Prize in Physiology or Medicine in 2016. 

After a time, metabolism in the Alzheimer brain usually declines, which contributes to the degradation of synapses. This the researchers could also see in the older mice, which had had the disease for a longer time.