Category Archives: Psychiatry

Problems In Thinking And Attention Linked To COVID-19 Infection (Psychiatry)

Evidence of cognitive deficits in people who have recovered from COVID-19 has been discovered in a new study of over 80,000 individuals.

The research found that those with more severe COVID-19 symptoms scored lower on an online series of tests, with performance on reasoning and problem-solving tasks being most affected. Further analysis of the data indicated that those who received mechanical ventilation to help them breathe whilst in hospital had the greatest impairment on cognitive tasks.

Published in the journal EClinicalMedicine, the research was a collaboration between King’s College London, Imperial College London and Cambridge University. It was part-funded by the UK Dementia Research Institute Care Research & Technology Centre and the National Institute of Health Research (NIHR) Maudsley Biomedical Research Centre.

Online cognition tests

A series of online tests, developed by first author on the study and Reader in Restorative Neuroscience at Imperial College London Dr Adam Hampshire had been opened up to the general public just before the pandemic for the BBC2 Horizon’s Great British Intelligence test. In early 2020 the study team extended the questionnaires to gather information on SARS-CoV-2 infection, the symptoms experienced and the need for hospitalisation.

Out of the 81,337 who provided complete data, 12,689 people suspected they had COVID-19. Participants reported a range of severity of illness, with many experiencing respiratory symptoms whilst still being able to stay at home (3,559 participants). Nearly 200 were hospitalised (192 participants) and about a quarter of these (44 participants) required mechanical ventilation.

The time since illness onset was around 1-6 months, meaning the study could not draw any definitive conclusions about whether these effects on cognition were long-lasting.

Thinking problems and respiratory symptoms

The study found a relationship between deficits in overall cognitive performance and severity of respiratory symptoms experienced. The research also found that not all areas of thinking ability correlated in the same way with COVID-19 illness and that some abilities were spared, which included emotional discrimination (recognition of faces that were expressing the same emotion) and working memory (remembering where a sequence of squares appears on the screen). In comparison ‘executive’ tasks that required skills in reasoning (such as deciding if relationships between words were similar) and problem solving (working out how many moves it would take to go from one arrangement to another) seemed to show the greatest deficit.

To understand the size of the deficits the authors compared the pattern of scores on the tests to cognitive changes that occur for other reasons. The effects in those hospitalised with mechanical ventilation were similar to the average cognitive decline seen over a period of ten years of ageing and equivalent to a seven-point difference in IQ.

HampshireetalInfoGraphicEdit

Ruling out other explanations

The researchers carried out a series of checks to ensure these cognitive deficits were associated with COVID-19 and not explicable by other variables. These included separating out those who had a confirmed positive test for SARS-CoV-2 and demonstrating that the cognitive deficits were indeed greater in those with positive tests. Further checks suggested the results were not due to a minority with pre-existing conditions or on-going symptoms of COVID-19. Analysis also indicated that it was unlikely that the results could be explained by the fact that those who contracted more severe COVID-19 disease were less cognitively able before they were ill.

Dr Adam Hampshire, first author on the study, said: “Our study adds to an increasing body of research that is looking at different aspects of how COVID-19 might be impacting the brain and brain function. This research is all converging to indicate that there are some important effects of COVID-19 on the brain that need further investigation. Going forward it would be valuable to bring together brain imaging and cognitive tests with other information on mental health and everyday function, ideally in studies that track people’s trajectories for months or even years. To really know what the long-term effects are for people will require people to be followed up over time.”

New studies, such as COVID-19 Clinical Neuroscience Study (COVID-CNS), led by King’s College London and University of Liverpool and the REACT Long COVID study, led by Imperial College London, are now applying these cognitive tools to study the long-term impacts of COVID-19.

“A critical question remains as to why some cognitive functions are more affected than others,” said Mitul Mehta, Professor of Neuroimaging from King’s College London and senior author on the study. “It is already known that hypoxia and mechanical ventilation are associated with cognitive deficits similar to those observed in this study, and there is now evidence of neurological complications in some patients, as well as psychiatric consequences. As we are coming through the third wave of the pandemic, there are more available options that can reduce the severity of COVID-19 such as vaccination and effective treatments whilst in hospital. The findings from this study suggest that by reducing the severity of illness through these different approaches we may also be able to reduce the severity of cognitive difficulties people may experience.”

The research paper ‘Cognitive deficits in people who have recovered from COVID-19’ was published online first in EClinicalMedicine on 22 July 2021.

All Images credit: KCL


Provided by King’s College London

New Findings On How Ketamine Acts Against Depression (Psychiatry)

The discovery that the anaesthetic ketamine can help people with severe depression has raised hopes of finding new treatment options for the disease. Researchers at Karolinska Institutet have now identified novel mechanistic insights of how the drug exerts its antidepressant effect. The findings have been published in the journal Molecular Psychiatry.

Portrait photo of Per Svenningsson, professor at the Department of Clinical Neuroscience
Per Svenningsson. Photo: Ulf Sirborn.

According to the World Health Organization, depression is a leading cause of disability worldwide and the disease affects more than 360 million people every year.

The risk of suffering is affected by both genetics and environmental factors. The most commonly prescribed antidepressants, such as SSRIs, affect nerve signalling via monoamines in the brain.

However, it can take a long time for these drugs to help, and over 30 percent of sufferers experience no relief at all.

The need for new types of antidepressants with faster action and wider effect is therefore considerable.

An important breakthrough is the anaesthetic ketamine, which has been registered for some years in the form of a nasal spray for the treatment of intractable depression.

Relieves depressive symptoms quickly

Unlike classic antidepressants, ketamine affects the nerve signalling that occurs via the glutamate system, but it is unclear exactly how the antidepressant effect is mediated. When the medicine has an effect, it relieves depressive symptoms and suicidal thoughts very quickly.

However, ketamine can cause unwanted side effects such as hallucinations and delusions and there may be a risk of abuse so alternative medicines are needed.

The researchers want to better understand how ketamine works in order to find substances that can have the same rapid effect but without the side effects.

Explains ketamine’s effects

In a new study, researchers at Karolinska Institutet have further investigated the molecular mechanisms underlying ketamine’s antidepressant effects. Using experiments on both cells and mice, the researchers were able to show that ketamine reduced so-called presynaptic activity and the persistent release of the neurotransmitter glutamate.

“Elevated glutamate release has been linked to stress, depression and other mood disorders, so lowered glutamate levels may explain some of the effects of ketamine,” says Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet, and the study’s last author.

When nerve signals are transmitted, the transmission from one neuron to the next occurs via synapses, a small gap where the two neurons meet.

The researchers were able to see that ketamine directly stimulated AMPA receptors, which sit postsynaptically, that is, the part of the nerve cell that receives signals and this leads to the increased release of the neurotransmitter adenosine which inhibits presynaptic glutamate release.

The effects of ketamine could be counteracted by the researchers inhibiting presynaptic adenosine A1 receptors.

“This suggests that the antidepressant action of ketamine can be regulated by a feedback mechanism. It is new knowledge that can explain some of the rapid effects of ketamine,” says Per Svenningsson

In collaboration with Rockefeller University, the same research group has also recently reported on the disease mechanism in depression.

The findings, also published in the journal Molecular Psychiatry, show how the molecule p11 plays an important role in the onset of depression by affecting cells sitting on the surface of the brain cavity, ependymal cells, and the flow of cerebrospinal fluid.

Featured image: Illustration of depression © Getty Images.


Publications

“Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors”, Vesna Lazarevic, Yunting Yang, Ivana Flais, Per Svenningsson. Molecular Psychiatry, 11 August 2021, doi: 10.1038/s41380-021-01246-3.

“Ependymal cells-CSF flow regulates stress-induced depression”, Ji-Seon Seo, Ioannis Mantas, Per Svenningsson and Paul Greengard. Molecular Psychiatry, 7 July 2021 doi: 10.1038/s41380-021-01202-1.


Provided by Karolinska Institute

Patients with Early-onset Schizophrenia Have Already Exhibited Alteration in Their Brain Structural Network Globally and Regionally (Psychiatry)

Schizophrenia is a neurodevelopmental disorder characterized by both brain structural and functional abnormalities. Most of the existing findings, however, were limited to adult patients with established schizophrenia with a long duration of illness. It is still not clear whether the altered brain structural and functional abnormalities observed in adult patients have also been exhibited in children and adolescents with schizophrenia.

In order to address this issue, Dr. Raymond Chan’s team from the Institute of Psychology of the Chinese Academy of Sciences and his collaborators have recruited 25 individuals (aged 10-15 years) with early-onset schizophrenia (EOS) and 31 typically-developing (TD) controls to specifically examine whether structural connectivity with different brain regions has been altered during childhood onset schizophrenia.

Their findings showed that patients with EOS exhibited significantly increased clustering and local efficiency across a range of network densities comparing to TD controls.

They also found that the network of patients with EOS also demonstrated more modules than their TD counterparts, indicating a more segregated network at the cost of functional integration, especially in the prefrontal cortex, the hippocampus and the cerebellum.

Interestingly, patients with EOS did not exhibit the typical left-hemispheric-dominant hub distribution compared with the TD controls. Bearing the relatively small sample and the preliminary nature of the study, these findings did suggest that patients with early onset schizophrenia have already exhibited alteration in their brain structural network both globally and regionally.

The study was supported by the National Key Research and Development Programme of China, the China Postdoctoral Science Foundation, the Humanity and Social Science Youth foundation of the Ministry of Education, and the CAS Key Laboratory of Mental Health of the Institute of Psychology.

The study is now published online on Psychiatry Research Neuroimaging with the title of “Altered topographical organization of grey matter structural network in early-onset schizophrenia” on July 31.


Reference: Han-yu Zhou, Li-juan Shi, Yan-mei Shen, Yu-min Fang, Yu-qiong He, Hua-bing Li, Xue-rong Luo, Eric F.C. Cheung, Raymond C.K. Chan, Altered topographical organization of grey matter structural network in early-onset schizophrenia, Psychiatry Research: Neuroimaging, Volume 316, 2021, 111344, ISSN 0925-4927, https://doi.org/10.1016/j.pscychresns.2021.111344. (https://www.sciencedirect.com/science/article/pii/S0925492721000962)


Provided by Chinese Academy of Sciences

A Machine Learning Approach For Predicting Risk of Schizophrenia Using A Blood Test (Psychiatry)

An innovative strategy that analyzes specific regions of the genome offers the possibility of early diagnosis of schizophrenia, reports a team led by researchers at Baylor College of Medicine. The strategy applied a machine learning algorithm called SPLS-DA to analyze specific regions of the human genome called CoRSIVs, hoping to reveal epigenetic markers for the condition.  

In DNA from blood samples, the team identified epigenetic markers, a profile of methyl chemical groups in the DNA, that differ between people diagnosed with schizophrenia and people without the disease and developed a model that would assess an individual’s probability of having the condition. Testing the model on an independent dataset revealed that it can identify schizophrenia patients with 80% accuracy. The study appears in the journal Translational Psychiatry.

“Schizophrenia is a devastating disease that affects about 1% of the world’s population,” said corresponding author  Dr. Robert A. Waterland professor of pediatrics – nutrition at the USDA/ARS Children’s Nutrition Research Center at Baylor and of molecular and human genetics. “Although genetic and environmental components seem to be involved in the condition, current evidence only explains a small portion of cases, suggesting that other factors, such as epigenetic, also could be important.”

Epigenetics is a system for molecular marking of DNA – it tells the different cells in the body which genes to turn on or off in that cell type, therefore epigenetic markers can vary between different normal tissues within one individual. This makes it challenging to assess whether epigenetic changes contribute to diseases involving the brain, like schizophrenia.

To address this obstacle, Waterland and his colleagues had identified in previous work a set of specific genomic regions in which DNA methylation, a common epigenetic marker, differs between people but is consistent across different tissues in one person. They called these genomic regions CoRSIVs for correlated regions of systemic interindividual variation. They proposed that studying CoRSIVs is a novel way to uncover epigenetic causes of disease.

“Because methylation patterns in CoRSIVs are the same in all the tissues of one individual, we can analyze them in a blood sample to infer epigenetic regulation on other parts of the body that are difficult to assess, such as the brain,” Waterland said.

Many previous studies have analyzed methylation profiles in blood samples with the goal of identifying epigenetic differences between individuals with schizophrenia, the researchers explained.

“Our study is innovative in various ways,” said first author Dr. Chathura J. Gunasekara, computer scientist in the Waterland lab. “We focused on CoRSIVs and also applied for the first time the SPLS-DA machine learning algorithm to analyze DNA methylation. As a scientist interested in applying machine learning to medicine, our findings are very exciting. They not only suggest the possibility of predicting risk of schizophrenia early in life, but also outline a new approach that may be applicable to other diseases.”

The current study also is innovative because it considered major potential confounding factors other studies did not take into account. For instance, methylation patterns in blood can be affected by factors such as smoking and taking antipsychotic medications, both of which are common in schizophrenia patients.

“Here, we took various approaches to evaluate whether the methylation patterns we detected at CoRSIVs were affected by medication use and smoking. We were able to rule that out,” Waterland said. “This, together with the fact that DNA methylation at CoRSIVs is established very early in life, indicates that the epigenetic differences we identified between schizophrenia patients and healthy individuals were there before the disease was diagnosed, suggesting they may contribute to the condition.”

Using this novel approach, the researchers were able to achieve much stronger epigenetic signals associated with schizophrenia than has ever been done before, said the team.

“We consider our study a proof of principle that focusing on CoRSIVs makes epigenetic epidemiology possible,” Waterland said.

The following authors also contributed to this work: Eilis Hannon and Jonathan Mill at University of Exeter Medical School, Harry MacKay and Cristian Coarfa at Baylor College of Medicine, Andrew McQuillin at University College London and David St. Clair at University of Aberdeen.

This work was supported by NIH/NIDDK (grant number 1R01DK111522), the Cancer Prevention and Research Institute of Texas (grant number RP170295) and USDA/ARS (CRIS 3092-5-001-059).


Provided by Baylor College of Medicine

A New Way To Treat PTSD? (Psychiatry)

Exposure to a traumatic experience can lead to post-traumatic stress disorder (PTSD), an incapacitating disorder in susceptible persons with no reliable therapy. Particularly puzzling is understanding how transient exposure to trauma creates persistent long- term suffering from PTSD and why some people are susceptible to PTSD while others that were exposed to the same trauma remain resilient.

Epigenetic modifications are chemical marks on genes that program their activity. These marks are written into DNA during fetal development to correctly program how our genes function in different organs. However, research in the last two decades has suggested that these marks could also be modulated by experiences and exposures at different point of time in life. Studies in humans have suggested that perhaps the initial trauma exposure results in “epigenetic alterations” that in turn mediate and embed the PTSD disorder. These ideas were based on analysis of blood DNA of humans with PTSD, but it was not known whether epigenetic changes play a causal role in the brain regions that are considered important for PTSD.

A team of scientists from Bar-Ilan University, led by Prof. Gal Yadid, of the Mina and Everard Goodman Faculty of Life Sciences and Gonda (Goldschmied) Multidisciplinary Brain Research Center, examined this question using an animal PTSD model and discovered a new way for treating PTSD that might be applied to humans. Their findings were recently published in the Nature journal Molecular Psychiatry.

The researchers first mapped ‘epigenetic DNA methylation marks’ in a brain region which is important for PTSD. They found distinct epigenetic differences between animals that were exposed to trauma and were resilient, and those animals that were exposed to trauma and were susceptible and developed PTSD-like behavior. The researchers found that an important ‘epigenetic’ enzyme that transfers methyl groups onto DNA, DNMT3A, is reduced in animals that are susceptible to PTSD. The researchers also searched for groups of genes whose methylation is altered in the PTSD susceptible animals and found that one group of genes is controlled by the retinoic acid receptor which is activated by vitamin A. Indeed, delivering DNMT3A or retinoic acid orphan receptor gene into the animal brains reverses the PTSD-like phenotypes, suggesting that these genes that are differentially methylated are responsible for PTSD behavior.

Injecting brains with genes is still not a feasible therapeutic option. Therefore, the authors tested whether nutritional supplements that mimic the activity of these genes could treat and reverse PTSD in susceptible animals. Since DNMT3A increases DNA methylation, the researchers used a natural product that donates methyl groups S-adenosylmethionine (SAMe) and to activate the retinoic acid receptor they treated the animals with vitamin A.  They found that combined treatment with the methyl donor SAM and retinoic acid reversed PTSD-like behaviors.

The data suggest a novel approach to treatment of PTSD, which involves combining two natural products that modulate the epigenome. Importantly, epigenetic treatments reverse the underlying causes of the disorder on DNA and thus serve as a “cure” rather than temporary relief of symptoms. “Since these nutritional supplements are relatively nontoxic, they offer hope for a nontoxic treatment of PTSD that reverses the underlying genomic cause of the disease,” said Prof. Yadid.


Reference: Gal Warhaftig et al, Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy, Molecular Psychiatry (2021). DOI: 10.1038/s41380-021-01178-y


Provided by Bar-Ilan University

Discovery Points To Ketamine’s Long-term Antidepressant Effects (Psychiatry)

THE IDEA

Building on recent research confirming how ketamine induces rapid antidepressant action, Professor of Pharmacology Lisa Monteggia and her collaborators show how the molecular mechanism of the gene MeCP2 and associated synaptic adaptability are critical to the long-term antidepressant effects of ketamine.

While MeCP2 has been shown to be important for typical antidepressants, this research indicates that, in cooperation with ketamine’s initial target, the gene is important for long-term antidepressant action, Monteggia said. The researchers discovered that MeCP2 influences ketamine’s behavioral effect as well as potentiation—the strengthening of synapses—improving its antidepressant effects over time. This work also shows that the long-term effects of ketamine involve synaptic adaptability, or plasticity—not simply structural changes. Monteggia and her team went on to show that repeated exposure to ketamine further strengthened synaptic plasticity—eliciting more plasticity of plasticity—which the team termed “metaplasticity.” This may explain why repeated doses of ketamine produce a cumulative and prolonged effect.

Lisa Monteggia
Lisa Monteggia © Vanderbilt University

WHY IT MATTERS

“We think we have the pathway in the brain to engage these long-term effects,” said Monteggia, also director of the Vanderbilt Brain Institute. “To have an impact on treatment or clinical drug development, you must know the processes in the brain that are involved. This is the first research that gives us an explanation for how ketamine produces long-term effects involving synaptic plasticity in the brain and why ketamine has cumulative antidepressant effects—a huge step forward.”

This discovery will allow researchers to target the neural pathway that prolongs ketamine’s antidepressant effects without the drug itself. While ketamine has significant promise, it also carries abuse liabilities, as the drug can trigger psychomedical effects. At low doses the drug is not harmful, but no one knows the outcome of sustained use of ketamine to date. This discovery may be a way to circumvent the unintended and still unknown negative effects of ketamine exposure.

WHAT’S NEXT

With the knowledge that MeCP2 can regulate gene expression, researchers are now looking to understand the neural pathway of the gene more fully, and to find commonalities with common antidepressants to extend their effects.

FUNDING

This work was supported by National Institutes of Health grants MH070727, MH081060 and MH066198, the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education grant 2016R1A6A3A03008533, and the Swedish Pharmaceutical Society and the Swedish Society for Medical Research.

GO DEEPER

The article “Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation” was published in the journal Nature Neuroscience on June 28.

Collaborators on this research include Ege Kavalali, professor of pharmacology and William Stokes Chair in Experimental Therapeutics, and Vanderbilt postdoctoral researcher Ji-Woon Kim, as well as Anita Autry of Albert Einstein College of Medicine, Elisa Na of Texas Woman’s University, Megumi Adachi of Astellas Pharma, and Carl Bjorkholm of University of Texas Southwestern Medical Center.


Provided by Vanderbilt University

Study Strengthens Argument Postpartum Depression Different To Major Depression (Psychiatry)

Women with postpartum depression experience smell differently to other women, a University of Otago study has found.

Mei Peng image
Dr Mei Peng. © University of Otago

Lead author Dr Mei Peng, of the Department of Food Science, says the findings add further evidence to the growing argument postpartum depression is different to major depression, and requires separate research and medical attention.

“Postpartum depression has been long regarded as a sub-category of major depressive disorder. This condition has a very poor diagnostic rate, with many women suffering from it without being properly diagnosed or treated.

“Recently, the scientific community has been questioning whether postpartum depression should be studied and treated separately from major depression following insights into the different effect each disorder has on neurobiology,” she says.

Pregnancy-related depression is very common, with 6–12 per cent of women being affected during pregnancy, and more than 20 per cent being affected after having a baby. Resolving the status of postpartum depression may have important implications for diagnosis, treatment, policy and research of the disorder.

“Our world-first study helps show the sensory symptoms related to postpartum depression are very different from those of major depression. Specifically, patients with postpartum depression show normal olfactory sensitivity whereas generic depressed patients would show substantially declined olfactory sensitivity.”

The multi-disciplinary study, published in Scientific Reports, assessed the olfactory abilities of 39 depressed mothers, who were pregnant and up to one-year post pregnancy, comparing them against a healthy cohort.

The researchers found no difference between the two groups in terms of their ability to detect smells, but postpartum depressed women experienced different intensity and hedonic perception of some smells.

“These findings imply that postpartum depression is associated with alterations in higher-order olfactory perception, but not early-processing of odours.”

The researchers are currently seeking funding to further study the effects of pregnancy on women’s long-term quality of life.


Publication details:

Olfactory shifts linked to postpartum depression
Mei Peng, Hazel Potterton, JoannaTing Wai Chu and PaulGlue
Scientific Reports


Provided by University of Otago

Researchers Discovered How Levels Of A Protein Could be Used in the Future To Diagnose Schizophrenia (Psychiatry)

Scientists at Sanford Burnham Prebys have discovered how levels of a protein could be used in the future as a blood-based diagnostic aid for schizophrenia. The activity of the protein, which is found in both the brain and blood, affects neural connections in human brains and is uniquely imbalanced in people diagnosed with the condition. The research also provides guidance for future analyses into the molecular basis of this serious, disabling mental disorder.

The study, an international collaboration among groups at Yokohama City University Graduate School of Medicine in Japan and the Department of Psychiatry at Harvard Medical School in Belmont, Massachusetts, was recently published in PNAS.

“This study examined the activity of CRMP2, a protein found in the brain (called a ‘cytoskeletal protein’) that regulates how neurons make connections with each other,” says Evan Y. Snyder, M.D., Ph.D., director of the Center for Stem Cells and Regenerative Medicine at Sanford Burnham Prebys and co-senior author of the study. “CRMP2 also happens to be expressed in lymphocytes in the blood and can therefore be readily sampled in people by doing nothing more than a simple venipuncture.

“There was an abundance of CRMP2 levels in samples from people with schizophrenia compared to people without the disorder. We also saw structural abnormalities in the dendrites of neurons that could potentially be disabling because dendrites play an important role in receiving impulses from other nerve cells in the brain.”

Previous research has shown that most people maintain an even balance between the two forms of CRMP2: its active, non-phosphorylated form and its inactive, phosphorylated form. The new research first examined postmortem brain tissue and then blood samples from people with schizophrenia. The research team compared these levels to those in people without the disorder.

The findings indicated that the amount of active CRMP2 was too high in people with schizophrenia and, at least in young people with schizophrenia, was not balanced by an appropriate amount of increased inactive CRMP2. That imbalance between active and inactive CRMP2 could account for some dysfunctions in neural connections.

Measuring an abundance of active CRMP2, particularly if its ratio with inactive CRMP2 is too low, could become a format for a rapid, minimally invasive blood test to support the diagnosis of schizophrenia.

“Schizophrenia can be challenging to diagnose early on or in young patients for a number of reasons,” says Snyder. “Pairing a blood test with psychiatric and neurobehavioral exams could help doctors distinguish schizophrenia from other conditions that have somewhat similar symptomologies, such as the manic phase of bipolar disorder or other behavioral, personality, or thought disorders.

“Our results were most striking in people under the age of 40, and even more so in people under the age of 30. An early diagnosis could improve the clinical management of affected individuals as well as accelerate the development of new therapeutic options,” Snyder adds.

The researchers now want to dig deeper into the molecular biology of the disease to discover the “regulator” that keeps most people’s CRMP2 levels on an even keel. They also want to conduct a larger, multi-center clinical study that compares schizophrenia with other psychiatric disorders. Future research will aim to include a wider range of ethnicities and age groups.

Featured image: Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.


Reference: Munetaka Nomoto el al., “Clinical evidence that a dysregulated neural network modulator may aid in diagnosing schizophrenia,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2100032118


Provided by Sanford Burnham Prebys Medical Discovery Institute

Scientists Reverse Age-related Memory Loss in Mice (Psychiatry)

Scientists at Cambridge and Leeds have successfully reversed age-related memory loss in mice and say their discovery could lead to the development of treatments to prevent memory loss in people as they age.

“Although our study was only in mice, the same mechanism should operate in humans – the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age.”

— James Fawcett

In a study published in Molecular Psychiatry, the team show that changes in the extracellular matrix of the brain – ‘scaffolding’ around nerve cells – lead to loss of memory with ageing, but that it is possible to reverse these using genetic treatments.

Recent evidence has emerged of the role of perineuronal nets (PNNs) in neuroplasticity – the ability of the brain to learn and adapt – and to make memories. PNNs are cartilage-like structures that mostly surround inhibitory neurons in the brain. Their main function is to control the level of plasticity in the brain. They appear at around five years old in humans, and turn off the period of enhanced plasticity during which the connections in the brain are optimised. Then, plasticity is partially turned off, making the brain more efficient but less plastic.

PNNs contain compounds known as chondroitin sulphates. Some of these, such as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulphate, promote neuroplasticity. As we age, the balance of these compounds changes, and as levels of chondroitin 6-sulphate decrease, so our ability to learn and form new memories changes, leading to age-related memory decline.

Researchers at the University of Cambridge and University of Leeds investigated whether manipulating the chondroitin sulphate composition of the PNNs might restore neuroplasticity and alleviate age-related memory deficits.

To do this, the team looked at 20-month old mice – considered very old – and using a suite of tests showed that the mice exhibited deficits in their memory compared to six-month old mice.

For example, one test involved seeing whether mice recognised an object. The mouse was placed at the start of a Y-shaped maze and left to explore two identical objects at the end of the two arms. After a short while, the mouse was once again placed in the maze, but this time one arm contained a new object, while the other contained a copy of the repeated object. The researchers measured the amount of time the mouse spent exploring each object to see whether it had remembered the object from the previous task. The older mice were much less likely to remember the object.

The team treated the ageing mice using a ‘viral vector’, a virus capable of reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs and found that this completely restored memory in the older mice, to a level similar to that seen in the younger mice.

Dr Jessica Kwok from the School of Biomedical Sciences at the University of Leeds said: “We saw remarkable results when we treated the ageing mice with this treatment. The memory and ability to learn were restored to levels they would not have seen since they were much younger.”

To explore the role of chondroitin 6-sulphate in memory loss, the researchers bred mice that had been genetically-manipulated such that they were only able to produce low levels of the compound to mimic the changes of ageing. Even at 11 weeks, these mice showed signs of premature memory loss. However, increasing levels of chondroitin 6-sulphate using the viral vector restored their memory and plasticity to levels similar to healthy mice.

Professor James Fawcett from the John van Geest Centre for Brain Repair at the University of Cambridge said: “What is exciting about this is that although our study was only in mice, the same mechanism should operate in humans – the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age.”

The team have already identified a potential drug, licensed for human use, that can be taken by mouth and inhibits the formation of PNNs. When this compound is given to mice and rats it can restore memory in ageing and also improves recovery in spinal cord injury. The researchers are investigating whether it might help alleviate memory loss in animal models of Alzheimer’s disease.

The approach taken by Professor Fawcett’s team – using viral vectors to deliver the treatment – is increasingly being used to treat human neurological conditions. A second team at the Centre recently published research showing their use for repairing damage caused by glaucoma and dementia.

The study was funded by Alzheimer’s Research UK, the Medical Research Council, European Research Council and the Czech Science Foundation.

Featured image: Spatially oriented model (mouse brain) © University of Cambridge


Reference
Yang, S et al. Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing. Molecular Psychiatry; 16 July 2021; DOI: doi.org/10.1038/s41380-021-01208-9


Provided by University of Cambridge