Researchers at Karolinska Institute have charted a highly detailed molecular atlas of the foetal development of the brain.
The study, published in Nature, made use of single-cell technology which was performed on mice. In this way, researchers have identified almost 800 different cells that are active during foetal development – far more than previously known.
“Brain development is well described and the main cell types are known. What is new about our atlas is the high resolution and detail,” said Sten Linnarsson, head of research and professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
In their work, the researchers followed the brain development of the mice from day seven, when the brain is just forming, to the end of pregnancy on day 18.
Using single-cell technology, they were able to identify the detailed composition of the brain during foetal development: what cell types exist, how many cells of each type, and how this changes at the various stages of development.
The researchers also studied gene activity in each individual cell, classifying cells according to these activity patterns.
Creating a molecular atlas
The result is a molecular atlas that accurately illustrates how all cells in the brain develop from the early embryo. The atlas shows, for example, the way early neural stem cells first increase and then decrease in number, being replaced by transitional forms in several waves that eventually mature into ready-made neurons.
The researchers also demonstrated how early stem cell lines branch much like a family tree, giving rise to several different types of mature cells. The next step is mapping out atlases of the human brain, both in adults and during foetal development.
“Atlases like this are of great importance for research into the brain, both to understand brain function and its diseases. Cells are the body’s basic building blocks and the body’s diseases are always expressed in specific cells. Genes that cause serious diseases are found in all of the body’s cells, but they cause disease only in specific cells in the brain,” said Prof Linnarsson.
A new study adds to the growing body of evidence that decisions regarding moderate-to-severe traumatic brain injury (TBI) should not be made too soon after the injury, as a good prognosis can still emerge.
Researchers followed 484 patients with moderate-to-severe TBI and found that among the patients in a vegetative state, one quarter “regained orientation” — awareness of who, when and where they were — within 12 months of their injury.
“Withdrawal of life-sustaining treatment based on early prediction of poor outcome accounts for most deaths in patients hospitalised with severe TBI,” said senior author Geoffrey Manley, MD, PhD, noting that 64 of the 92 fatalities in the study occurred within two weeks of injury. Dr Manley is professor and vice chair of neurological surgery at UCSF and chief of neurosurgery at Zuckerberg San Francisco General Hospital.
“TBI is a life-changing event that can produce significant, lasting disability, and there are cases when it is very clear early on that a patient will not recover,” he said. “But results from this study show a significant proportion of our participants experienced major improvements in life functioning, with many regaining independence between two weeks and 12 months after injury.”
The patients in the study were enrolled by the brain injury research initiative TRACK-TBI, of which Dr Manley is the principal investigator. All patients were 17 and older and had presented to hospitals with level 1 trauma centers within 24 hours of injury. Their exams met criteria for either moderate TBI or severe TBI. The causes were falls, assault and primarily crashes involving a motor vehicle.
The patients, whose average ages were 35 in the severe TBI group (78 percent males) and 38 in the moderate TBI group (80 percent males), were assessed using the Glasgow Outcomes Scale Extended (GOSE), which ranges from 1 for death to 8 for “upper good recovery” and resumption of normal life. Impairment was also categorised with the Disability Rating Scale (DRS).
At two weeks post-injury, 93 percent of the severe TBI group and 79 percent of the moderate TBI group had moderate-to-severe disability, according to the DRS, and 80 percent had GOSE scores from 2 to 3, meaning they required assistance in basic everyday functioning.
But by 12 months, half of the severe TBI group and three-quarters of the moderate TBI group had GOSE scores of at least 4, indicating they could function independently at home for at least eight hours per day. Moreover, 19 percent of the severe TBI group had no disability, according to the DRS, and a further 14 percent had only mild injury, the researchers noted.
Most surprising were the findings for the 62 surviving patients who had been in a vegetative state. By the 12-month mark all patients had recovered consciousness and 1 in 4 had regained orientation. All but one survivor in this group recovered at least basic communication ability.
“These patients made the cut for favorable outcome,” said co-first author, Joseph Giacino, PhD, of Spaulding Rehabilitation Hospital, Massachusetts General Hospital and Harvard Medical School. “Their GOSE scores were 4 or higher, which meant they could be at home unsupervised for at least eight hours a day, since they were able to take care of basic needs, such as eating and toileting.”
In prior work, a significant percentage of patients with grave impairments had been shown to achieve favorable functionality after many months or years. This study coincided with the recommendation in 2018 from the American Academy of Neurology that in the first 28 days after injury, clinicians should refrain from telling families that a patient’s prognosis is beyond hope.
“While a substantial proportion of patients die or suffer lasting disability, our study adds to growing evidence that severe acute impairment does not portend uniformly poor long-term outcome,” said Manley, who is also affiliated with the UCSF Weill Institute for Neurosciences. “Even those patients in a vegetative state – an outcome viewed as dire – may improve, since this is a dynamic condition that evolves over the first year.”
A Chinese study has found that the ability to sense nervous signals such as heartbeat varies with age, peaking in young adulthood, but does not seem to be associated with autism.
Interoception is the ability to process and integrate internal signals originating from one’s body, such as heartbeats and breathing patterns. This ability is important for maintaining homeostasis. Recent findings have suggested that autism spectrum disorders are associated with a wide range of sensory integration impairments including interoceptive accuracy.
However, it is still not clear whether individuals with subclinical features of autism, which only moderately impact daily life, also exhibit similar impairments in interoceptive accuracy. It is also not clear how interoceptive ability and its association with autistic traits varies with age.
In order to address this issue, Dr Raymond Chan’s team from the Institute of Psychology of the Chinese Academy of Sciences (CAS) has developed an innovative paradigm involving eye-tracking measures to examine the multidimensional interoception and autistic traits in different age groups.
In so doing, they recruited 114 healthy university students aged 19–22 and explored the correlations among autistic traits and interoceptive accuracy using an “Eye-tracking Interoceptive Accuracy Task” (EIAT), which presents two bouncing shapes and requires participants to look at the one whiches bounces in time with their heartbeat.
Since this task requires no verbal report or button-pressing, it enables the exploration of interoceptive accuracy in preschool children and individuals with psychiatric disorders or speech impairments.
However, while autistic traits correlated significantly with the ability to describe and express emotion (alexithymia) but not with the different dimensions of interoception such as interoceptive accuracy (performance of interoceptive ability on behavioural tests), interoceptive sensibility (subjective sensitivity to internal sensations on self-report questionnaires) and interoceptive awareness (personal insight into interoceptive aptitude).
They then recruited 52 preschool children aged four to six, 50 adolescents aged 12–16 and 50 adults aged 23–54 to specifically examine the relationship of autistic traits and interoceptive accuracy across these three age groups. The researchers found that interoceptive accuracy evolves from childhood to early adulthood, and then declines with age. The highest average accuracy was seen in 12-16 year olds. The dataset showed that the developmental trajectory of interoceptive accuracy has a reverted U-shape trend peaking around early adulthood.
The findings suggest that interoceptive accuracy significantly differs between typically-developing preschool children, adolescents and adults. The study also highlights the need for future study into preschool children with suspected autism spectrum disorders.
According to a new study, antibiotic exposure early in life could alter human brain development in areas responsible for cognitive and emotional functions.
The study suggests that penicillin alters the body’s microbiome as well as gene expression, which allows cells to respond to its changing environment, in key areas of the developing brain. The findings, published in the journal iScience, suggest reducing widespread antibiotic use or using alternatives when possible to prevent neurodevelopment problems. Penicillin and related medicines, such as ampicillin and amoxicillin, are the most widely used antibiotics in children worldwide. In the United States, the average child receives nearly three courses of antibiotics before age 2, and similar or greater exposure rates occur elsewhere.
“Our previous work has shown that exposing young animals to antibiotics changes their metabolism and immunity. The third important development in early life involves the brain. This study is preliminary but shows a correlation between altering the microbiome and changes in the brain that should be further explored,” said lead author Martin Blaser, director of the Center for Advanced Biotechnology and Medicine at Rutgers.
In the study, mice were exposed to low-dose penicillin in utero or immediately after birth. Researchers found that, compared to the unexposed controls, mice given penicillin had large changes in their intestinal microbiota, with altered gene expression in the frontal cortex and amygdala. These two key brain areas are responsible for the development of memory as well as fear and stress responses.
Increasing evidence links conditions in the intestine to the brain in the ‘gut-brain axis‘. If this pathway is disturbed, it can lead to permanent altering of the brain’s structure and function and possibly lead to neuropsychiatric or neurodegenerative disorders in later childhood or adulthood.
“Early life is a critical period for neurodevelopment,” Blaser said. “In recent decades, there has been a rise in the incidence of childhood neurodevelopmental disorders, including autism spectrum disorder, attention deficit/hyperactivity disorder and learning disabilities. Although increased awareness and diagnosis are likely contributing factors, disruptions in cerebral gene expression early in development also could be responsible.”
Whether it is antibiotics directly affecting brain development or if molecules from the microbiome travelling to the brain, disturbing gene activity and causing cognitive deficits needs to be determined by future studies.
Scientists have found that significant amounts of THC and CBD, the two main components of cannabis enter the embryonic brain of mice in utero and impair the mice’s ability as adults to respond to fluoxetine (Prozac).
The study suggests that when the developing brain is exposed to THC or CBD, normal interactions between endocannabinoid and serotonin signaling may be diminished as exposed individuals become adults.
“Hemp-derived CBD is a legal substance in the US, and we are in a time of increasing state-level legalisation of cannabis. Therefore, use of cannabis components have increased across most levels of society, including among pregnant women. The study marks the beginning of an effort to understand the effects of THC and CBD on the endogenous cannabinoid system (ECS) in the developing brain and body,” explained Hui-Chen Lu, director of the Linda and Jack Gill Center and professor in the Department of Psychological and Brain Sciences in the IU Bloomington College of Arts and Sciences.
Researchers studied four groups of pregnant mice. Some received daily moderate doses of either THC, CBD, or a combination of equal parts THC and CBD; a control group had placebo injections throughout pregnancy. Using mass spectrometry, IU psychological and brain sciences professor Heather Bradshaw tested embryos and found that CBD and THC both could cross the placenta and reach the embryonic brain.
“The surprising part is that maternal exposure to CBD alone — a drug that is often considered as safe and harmless and is a popular ‘natural’ therapy for morning sickness — resulted in a lasting impact on adult mice offspring,” Lu said. “Both prenatal THC and CBD exposure impaired the adult’s ability to respond to fluoxetine. The results suggest taking a cautious approach to using CBD during pregnancy.”
There is however some evidence for CBD’s effectiveness in treating chronic pain and anxiety, though currently the only FDA-approved indication for CBD is the treatment of severe seizure disorders.
“We still know very little about the effects of CBD on the developing brain,” Prof Lu said.
The new paper is one of the first studies to see the potential negative impact of CBD on the developing brain and later behaviours. However observational studies in the 1980s saw increased anxiety and depression in offspring of mothers who used the lower-strength cannabis available at the time. Since women may take cannabis products for nausea and vomiting, this has relevance for public health awareness.
Study co-author Ken Mackie, Gill Chair of Neuroscience at IU Bloomington, said researchers know that prenatal cannabis exposure may increase the risk for anxiety and depression, so it is important to evaluate the response to a class of drug used to treat anxiety and depression.
Though normal mouse behaviours were seen in many tests, one test — to determine their response to stress — had a strongly atypical result. In all groups, the mice responded normally to a stressful situation. As expected, fluoxetine increased stress resilience in mice whose mothers had received the placebo. However, the drug was ineffective in mice whose mothers had received THC, CBD or their combination.
Fluoxetine works by increasing the amount of serotonin available at brain synapses, an effect known to require the endocannabinoid system. This internal system of receptors, enzymes and molecules both mediates the effects of cannabis and plays a role in regulating various bodily systems, such as appetite, mood, stress and chronic pain.
To test if maternal exposure to THC and/or CBD impaired endocannabinoid signaling in the adult offspring, the researchers tested whether boosting the ECS with a drug would restore fluoxetine’s effectiveness. They found that the ECS boosting restored normal fluoxetine responses in mice that had received THC or CBD while their brains were developing.
Journal reference: de Sousa Maciel, I., et al. (2021) Perinatal CBD or THC Exposure Results in Lasting Resistance to Fluoxetine in the Forced Swim Test: Reversal by Fatty Acid Amide Hydrolase Inhibition. Cannabis and Cannabinoid Research. doi.org/10.1089/can.2021.0015.
Dopamine can help explain both autistic behaviours and men’s need for motivation or ‘passion’ in order to succeed compared to women’s ‘grit’, according to a new study.
Men – more often than women – need passion to succeed at things. At the same time, boys are diagnosed as being on the autism spectrum four times as often as girls. Both statistics may be related to dopamine, one of our body’s neurotransmitters.
“This is interesting. Research shows a more active dopamine system in most men” than in women, says Hermundur Sigmundsson, a professor at the Norwegian University of Science and Technology’s (NTNU) Department of Psychology.
He is behind a new study addressing gender differences in key motivating factors to excel in something. The study uses men’s and women’s differing activity in the dopamine system as an explanatory model. The study enrolled 917 participants aged 14 to 77, consisting of 502 women and 415 men.
“We looked at gender differences around passion, self-discipline and positive attitude,” said Prof Sigmundsson. The study refers to these qualities as passion, grit and mindset. The researchers also applied theories to possible links with dopamine levels. Dopamine, a neurotransmitter that is released in the brain, is linked to learning, attention and our ability to focus. It can contribute to a feeling of satisfaction.
Men generally secrete more dopamine, but it plays a far more complex role than simply being a ‘happy hormone’. Dopamine is linked to learning, attention and our ability to focus.Previous studies on Icelandic students have shown that men are more dependent on passion in order to succeed at something. This study confirms the earlier findings. In six out of eight test questions, men score higher on passion than women.
However, the association with dopamine levels has not been established previously.
“The fact that we’ve developed a test to measure passion for goal achievement means that we can now relate dopamine levels to passion and goal achievement,” explained Prof Sigmundsson.
Women, on the other hand, may have greater self-discipline – or grit – and be more conscientious, according to other studies. Their level of passion may not be as pronounced in general, but they are also able to use this to excel.
The results for the women, however, are somewhat more ambiguous than men’s need to have a passion for something, and this study found no such gender difference. Nor did the researchers find any difference between the sexes in terms of growth mindset.
Previous studies have associated the dopamine system with many different conditions, such as ADHD, psychoses, manias and Parkinson’s disease. However, it may also be related to a certain form of autistic behaviour.
Some individuals with autism may develop a deep interest in certain topics, something which others may find strange or even off putting. People on the autism spectrum can focus intensely on these topics or pursuits, at least for a while, and dopamine may play a role in this.
“Other research in neuroscience has shown hyperactivity in the dopamine system in individuals with autism, and boys make up four out of five children on the autism spectrum. This, and dopamine’s relationship to passion, might be a mechanism that helps to explain this behaviour,” concluded Prof Sigmundsson.
A new study from Duke and UNC scientists has discovered a crucial protein involved in the communication and coordination between astrocytes as they build synapses — essentially a brain building block.
Astrocytes, specialised, star-shaped glial cells that outnumber the neurons they support over fivefold and which make up about half the mass of a human brain, are increasingly being viewed as having a critical role in shaping the development of the brain. Astrocytes tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS, including guiding development of the brain.
The researchers found that a molecule, called hepaCAM, is a key component of this process. Without it, astrocytes aren’t as sticky as they should be, and tend to stick to themselves rather than forming connections with their neighbouring astrocytes.
This finding, in studies on mice with the gene for hepaCAM deleted from their astrocytes, helps in the understanding of several brain disorders, including cognitive decline, epilepsy and autism spectrum disorders.
One rare brain disorder, called megalencephalic leukoencephalopathy (MLC) is also known to be caused by a mutation in the hepaCAM gene, and this work might provide answers about what exactly has gone wrong. MLC is a developmental disorder that grows progressively worse, causing macrocephaly (a large head), swelling of the brain’s white matter, intellectual disability and epilepsy.
By deleting hepaCAM from astrocytes to see what it does, “we sort of made the cells into introverts,” explained senior author Cagla Eroglu, an associate professor of cell biology at the Duke University School of Medicine. “They’re normally wanting to reach out, but without hepaCAM, they started to hug themselves instead.”
“If the astrocyte makes junctions to its neighbours, then you start to have a network,” Prof Eroglu said. “To make a functional brain, you need a functional astrocytic network.”
The researchers zeroed in on hepaCAM by searching for highly active genes in astrocytes, and which have been implicated in brain dysfunction. They partnered with another group working on hepaCAM at the University of Barcelona, but that group has been looking at the molecule for its role in regulating chloride signaling channels in astrocytes.
The Duke group found that deleting hepaCAM from astrocytes led to a synaptic network that was too easily excited and not as well dampened. “The effect on the inhibitory synapses was the strongest,” said first author Katie Baldwin, who recently became an assistant professor of cell biology and physiology at the University of North Carolina at Chapel Hill. “You’re putting the inhibition down and the excitation up, so that really could point to a mechanism for epilepsy.”
Prof Baldwin plans to test whether hepaCAM-deficient mice have behavioural differences or changes in learning and memory, or whether they exhibit the stress and social anxiety that are markers of autism spectrum disorders. She said they might also reintroduce the disease-mutation versions of the protein to mice that were born without it to see what effects it has.
“We know hepaCAM is interacting with itself between two astrocytes, but we don’t know what it’s interacting with at the synapse,” Prof Baldwin said. “We don’t know if it could be interacting with hepaCAM which is also found in the neurons, or if it could be some other protein that we don’t know about yet.
A new study has found that statin use in adults 65 years old or older is not associated with incident dementia, mild cognitive impairment (MCI) or decline in individual cognition domains.
Major health concerns in the elderly, cognitive decline and dementia affect about 10% of people over 60 years old. Statins are used to reduce low-density lipoprotein cholesterol, and are a fundamental treatment for prevention of primary and secondary cardiovascular disease (CVD) events. In 2012 the Food and Drug Administration issued a warning about cases of apparent short-term cognitive impairment with statin use, while acknowledging that the cardiovascular benefits outweigh their risks. Systematic reviews have since shown insufficient evidence on the impact of statins, and research has shown mixed results, with some showing a neurocognitive benefit of statins and others reporting a null effect.
“With statins being increasingly prescribed to older adults, their potential long-term effects on cognitive decline and dementia risk have attracted growing interest,” said lead author Zhen Zhou, PhD, Menzies Institute for Medical Research at the University of Tasmania. “The present study adds to previous research by suggesting that statin use at baseline was not associated with subsequent dementia incidence and long-term cognitive decline in older adults.”
Researchers of this study analysed data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. ASPREE was a large prospective, randomized placebo-controlled trial of daily low-dose aspirin with adults 65 or older. One of the key selection criteria of ASPREE was that participants had to have a score of 78 for the Modified Mini-Mental State Examination test, a screening test for cognitive abilities, at enrollment.
The study had 18 846 participants, grouped by their baseline statin use (31.3% of participants) versus non-statin use. The study aimed to measure outcomes including incident dementia and its subclassifications (probable Alzheimer’s disease [AD], mixed presentations); MCI and its subclassifications (MCI consistent with AD, MCI-other); changes in domain-specific cognition including global cognition, memory, language and executive function, and psychomotor speed; and in the composite of these domains.
After a median of 4.7 years of follow-up, researchers found 566 incident cases of dementia (including probable AD and mixed presentations). Compared with no statin use, statin use was not associated with risk of all-cause dementia, probable AD or mixed presentations of dementia. There were 380 incident cases of MCI found (including MCI consistent with AD and MCI-other). Compared to no statin use, statin use was not associated with risk of MCI, MCI consistent with AD or other MCI. No statistically significant difference in the change of composite cognition and any individual cognitive domains between statin users versus non-statin users was seen. However, researchers did find interaction effects between baseline cognitive ability and statin therapy for all dementia outcomes.
The researchers acknowledged several limitations, including observational study bias and lack of data on the length of prior use of statins; and the dose of statins was not recorded in the ASPREE trial, so their effects could not be fully explored. Researchers conclude the study must be interpreted with caution and will require confirmation by randomized clinical trials designed to explore the neurocognitive effects of statins in older populations.
In an accompanying editorial comment, Christie M. Ballantyne, MD, professor at Baylor College of Medicine in Houston, noted study limitations that the authors address, but agreed the findings suggest statins do not contribute to cognitive decline.
“Overall, the analysis was well done, and its main strengths are a large cohort with a battery of standardised tests that allowed the investigators to track both cognition and incidence of dementia and its subtypes over time,” Ballantyne said. “Lingering questions such as the one raised by this analysis regarding potential adverse effects of statins in individuals with mildly impaired cognition can only be answered in randomised controlled trials in the appropriate age group and population and with appropriate testing and adequate follow-up. In the meantime, practising clinicians can have confidence and share with their patients that short-term lipid lowering therapy in older individuals, including with statins, is unlikely to have a major impact on cognition.”
A new study has identified, in mice, specific cells and proteins that control the sneeze reflex.
Better understanding of what causes us to sneeze, and especially how neurons behave in response to allergens and viruses, may lead to treatments which can slow the spread of infectious respiratory diseases.
A tickle in the nose can help trigger a sneeze, which expels irritants and disease-causing pathogens. But the cellular pathways that control the sneeze reflex go far beyond the sinuses and have been poorly understood. Now, a team led by researchers at Washington University School of Medicine in St. Louis has identified, in mice, specific cells and proteins that control the sneeze reflex.
“Better understanding what causes us to sneeze — specifically how neurons behave in response to allergens and viruses — may point to treatments capable of slowing the spread of infectious respiratory diseases via sneezes,” said Qin Liu, PhD, an associate professor of anesthesiology and the study’s senior investigator.
“We study the neural mechanism behind sneezing because so many people, including members of my own family, sneeze because of problems such as seasonal allergies and viral infections,” explained Prof Liu, a researcher in the university’s Center for the Study of Itch and Sensory Disorders. “Our goal is to understand how neurons behave in response to allergies and viral infections, including how they contribute to itchy eyes, sneezing and other symptoms. Our recent studies have uncovered links between nerve cells and other systems that could help in the development of treatments for sneezing and for fighting infectious respiratory diseases.”
Sneezing is the most common and forceful way of spreading infectious droplets from respiratory infections. Over two decades ago, researchers discovered a sneeze-evoking region in the central nervous system, but since then there has been little progress in understanding the mechanism of the sneeze reflex at the cellular and molecular level.
For the new study, Prof Liu and her team used a mouse model to figure out which nerve cells send signals that make mice sneeze. The researchers exposed the mice to aerosolised droplets containing either histamine or capsaicin, a pungent compound made from chili peppers, both of which caused the mice to sneeze.
By examining nerve cells that already were known to react to capsaicin, Liu’s team was able to identify a class of small neurons linked to sneezing that was caused by that substance. The researchers then searched for neuropeptides that could transmit sneeze signals to those nerve cells, and hit upon a molecule called neuromedin B (NMB), which they found was required for sneezing.
By eliminating the NMD-sensitive neurons in the part of the nervous system that evoked sneezes in the mice, they blocked the sneeze reflex. Those neurons all make a protein called the neuromedin B receptor. In mice lacking that receptor, sneezing again was greatly reduced.
“Interestingly, none of these sneeze-evoking neurons were housed in any of the known regions of the brainstem linked to breathing and respiration,” Prof Liu said. “Although we found that sneeze-evoking cells are in a different region of the brain than the region that controls breathing, we also found that the cells in those two regions were directly connected via their axons, the wiring of nerve cells.”
By exposing part of the mouse brain to the NMB peptide, the researchers found they could directly stimulate the sneeze reflex, even though they had not been exposed to any capsaicin, histamine or other allergens.
Since many viruses and other pathogens are spread in part by aerosolised droplets, Prof Liu said it may be possible to limit the spread of those pathogens by targeting NMB or its receptor to limit sneezing in those known to be infected.
“A sneeze can create 20 000 virus-containing droplets that can stay in the air for up to 10 minutes,” Liu Prof explained. “By contrast, a cough produces closer to 3000 droplets, or about the same number produced by talking for a few minutes. To prevent future viral outbreaks and help treat pathological sneezing caused by allergens, it will be important to understand the pathways that cause sneezing in order to block them. By identifying neurons that mediate the sneeze reflex, as well as neuropeptides that activate these neurons, we have discovered targets that could lead to treatments for pathological sneezing or strategies for limiting the spread of infections.”
A new study has uncovered insights into white matter changes that occur during chronic traumatic encephalopathy (CTE), a progressive brain disease associated with repetitive head impacts. This discovery may help in identifying new targets for therapies.
CTE been diagnosed after death in the brains of American football players and other contact sport athletes as well as members of the armed services. The disease has been identified as causing impulsivity, explosivity, depression, memory impairment and executive dysfunction.
Though much prior research focused on repetitive head trauma leading to the development of abnormal tau, this study focused on white matter changes, particularly the oligodendrocytes which myelinate nerve sheaths. The results have been published online [PDF] in the journal Acta Neuropathologica.
“Research to date has focused on the deposition of abnormal tau in the gray matter in CTE. This study shows that the white matter undergoes important alterations as well. There is loss of oligodendrocytes and alteration of oligodendrocyte subtypes in CTE that might provide new targets for prevention and therapies,” explained corresponding author Ann McKee, MD, chief of neuropathology at VA Boston Healthcare, director of the BU CTE Center.
Dr McKee and her team isolated cellular nuclei from the postmortem dorsolateral frontal white matter in eight cases of CTE and eight matched controls. They conducted single-nucleus RNA-seq (snRNA-seq) with these nuclei, revealing transcriptomic, cell-type-specific differences between the CTE and control cases. In doing so, they discovered that the white matter in CTE had fewer oligodendrocytes and the oligodendroglial subtypes were altered compared to control tissue.
Since previous studies have largely focused on the CTE-specific tau lesion located in the cortex in the brain, these findings are particularly informative as they explain a number of features of the disease. “In comparison, the cellular death process occurring in white matter oligodendrocytes in CTE appears to be separate from the accumulation of hyperphosphorylated tau,” she said. “We know that the behavioural and mood changes that occur in CTE are not explained by tau deposition. This study suggests that white matter alterations are also important features of the disease, and future studies will determine whether these white matter changes play a role in the production of behavioral or mood symptoms in CTE, such as explosivity, violence, impulsivity, and depression.”