Category: Neurology

Categories : Injury & Trauma NeurologyTags :

Glasgow Coma Scale Joined by New Measures to Assess TBI

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Trauma centres in the United States will begin to test a new approach for assessing traumatic brain injury (TBI) that is expected to lead to more accurate diagnoses and more appropriate treatment and follow-up for patients.

The new framework, which was developed by a coalition of experts and patients from 14 countries and spearheaded by the National Institutes of Health (NIH), expands the assessment beyond immediate clinical symptoms. Added criteria would include biomarkers, CT and MRI scans, and factors such as other medical conditions and how the trauma occurred.

The framework appears in the May 20 issue of Lancet Neurology.

For 51 years, trauma centres have used the Glasgow Coma Scale to assess patients with TBI, roughly dividing them into mild, moderate, and severe categories, based solely on their level of consciousness and a handful of other clinical symptoms.

That diagnosis determined the level of care patients received in the emergency department and afterward. For severe cases, it also influenced the guidance doctors gave the patients’ families, including recommendations around the removal of life support. Yet, doctors have long understood that those tests did not tell the whole story.

“There are patients diagnosed with concussion whose symptoms are dismissed and receive no follow-up because it’s ‘only’ concussion, and they go on to live with debilitating symptoms that destroy their quality of life,” said corresponding author Geoffrey Manley, MD, PhD, professor of neurosurgery at UC San Francisco and a member of the UCSF Weill Institute for Neurosciences. “On the other hand, there are patients diagnosed with ‘severe TBI’ who were eventually able to live full lives after their families were asked to consider removing life-sustaining treatment.”

In the US, TBI resulted in approximately 70 000 deaths in 2021 and accounts for about half-a-million permanent disabilities each year. Motor vehicle accidents, falls, and assault are the most common causes.

New system will better match patients to treatments

Known as CBI-M, the framework comprises four pillars – clinical, biomarker, imaging, and modifiers – that were developed by working groups of federal partners, TBI experts, scientists, and patients.

“The proposed framework marks a major step forward,” said co-senior author Michael McCrea, PhD, professor of neurosurgery and co-director of the Center for Neurotrauma Research at the Medical College of Wisconsin in Milwaukee. “We will be much better equipped to match patients to treatments that give them the best chance of survival, recovery, and return to normal life function.”

The framework was led by the NIH National Institute of Neurological Disorders and Stroke (NIH-NINDS), for which Manley, McCrea, and their co-first and co-senior authors are members of the steering committee on improving TBI characterisation.

The clinical pillar retains the Glasgow Coma Scale’s total score as a central element of the assessment, measuring consciousness and pupil reactivity as an indication of brain function. The framework recommends including the scale’s responses to eye, verbal, and motor commands or stimuli, presence of amnesia, and symptoms like headache, dizziness, and noise sensitivity.

“This pillar should be assessed as first priority in all patients,” said co-senior author Andrew Maas, MD, PhD, emeritus professor of neurosurgery at the Antwerp University Hospital and University of Antwerp, Belgium. “Research has shown that the elements of this pillar are highly predictive of injury severity and patient outcome.”

Biomarkers, imaging, modifiers offer critical clues to recovery

The second pillar uses biomarkers identified in blood tests to provide objective indicators of tissue damage, overcoming the limitations of clinical assessment that may inadvertently include symptoms unrelated to TBI.

Significantly, low levels of these biomarkers determine which patients do not require CT scans, reducing unnecessary radiation exposure and health care costs. These patients can then be discharged. In those with more severe injuries, CT and MRI imaging – the framework’s third pillar – are important in identifying blood clots, bleeding, and lesions that point to present and future symptoms.

Source: University of California – San Francisco

Categories : NeurologyTags :

Study Sheds Light on How Autistic People Communicate

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There is no significant difference in the effectiveness of how autistic and non-autistic people communicate, according to a new study, challenging the stereotype that autistic people struggle to connect with others.

The findings, published in Nature Human Behaviour, suggest that social difficulties often faced by autistic people are more about differences in how autistic and non-autistic people communicate, rather than a lack of social ability in autistic individuals, experts say. 

Researchers hope the results of the study will help reduce the stigma surrounding autism, and lead to more effective communication support for autistic people.  

Direct communication

Autism is a lifelong neurodivergence and disability, and influences how people experience and interact with the world. 

Autistic people often communicate more directly and may struggle with reading social cues and body language, leading to differences in how they engage in conversation compared to non-autistic people. 

Story sharing

The study, led by experts from the University of Edinburgh, tested how effectively information was passed between 311 autistic and non-autistic people. 

Participants were tested in groups where everyone was autistic, everyone was non-autistic, or a combination of both. 

The first person in the group heard a story from the researcher, then passed it along to the next person. Each person had to remember and repeat the story, and the last person in the chain recalled the story aloud. 

The amount of information passed on at each point in the chain was scored to discern how effective participants were at sharing the story. Researchers found there were no differences between autistic, non-autistic, and mixed groups.  

Increased awareness

After the task, participants rated how much they enjoyed the interaction with the other participants, based on how friendly, easy, or awkward the exchange was.  

Researchers found that non-autistic people preferred interacting with others like themselves, and autistic people preferred learning from fellow autistic individuals. This is likely down to the different ways that autistic and non-autistic people communicate, experts say.  

The findings confirm similar findings from a previous smaller study undertaken by the same researchers. They say the new evidence should lead to increased understanding of autistic communication styles as a difference, not a deficiency.   

Autism has often been associated with social impairments, both colloquially and in clinical criteria. Researchers have spent a lot of time trying to ‘fix’ autistic communication, but this study shows that despite autistic and non-autistic people communicating differently it is just as successful. With opportunities for autistic people often limited by misconceptions and misunderstandings, this new research could lead the way to bridging the communication gap and create more inclusive spaces for all.

 Dr Catherine Crompton, Chancellor’s Fellow at the University of Edinburgh’s Centre for Clinical Brain Sciences

Categories : NeurologyTags :

Language Shapes how Sensory Experiences are Stored in the Brain

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A study in stroke patients shows the brain’s vision-language connection shapes object knowledge

A schematic view of the main findings, adapted from a brain figure in the study. Image credit: Adapted from Liu Bet al., 2025, PLOS Biology, CC-BY 4.0

Our ability to store information about familiar objects depends on the connection between visual and language processing regions in the brain, according to a study published May 20th in the open-access journal PLOS Biology by Bo Liu from Beijing Normal University, China, and colleagues.

Seeing an object and knowing visual information about it, like its usual colour, activate the same parts of the brain. Seeing a yellow banana, for example, and knowing that the object represented by the word “banana” is usually yellow, both excite the ventral occipitotemporal cortex (VOTC). However, there’s evidence that parts of the brain involved in language, like the dorsal anterior temporal lobe (ATL), are also involved in this process – dementia patients with ATL damage, for example, struggle with object colour knowledge, despite having relatively normal visual processing areas. To understand whether communication between the brain’s language and sensory association systems is necessary for representing information about objects, the authors tested whether stroke-induced damage to the neural pathways connecting these two systems impacted patients’ ability to match objects to their typical colour. They compared colour-identification behaviour in 33 stroke patients to 35 demographically-matched controls, using fMRI to record brain activity and diffusion imaging to map the white matter connections between language regions and the VOTC.

The researchers found that stronger connections between language and visual processing regions correlated with stronger object color representations in the VOTC, and supported better performance on object color knowledge tasks. These effects couldn’t be explained by variations in patients’ stroke lesions, related cognitive processes (like simply recognizing a patch of color), or problems with earlier stages of visual processing. The authors suggest that these results highlight the sophisticated connection between vision and language in the human brain.

The authors add, “Our findings reveal that the brain’s ability to store and retrieve object perceptual knowledge – like the colour of a banana – relies on critical connections between visual and language systems. Damage to these connections disrupts both brain activity and behaviour, showing that language isn’t just for communication – it fundamentally shapes how sensory experiences are neurally structured into knowledge.”

Provided by PLOS

Categories : Metabolic Disorders NeurologyTags :

Could the Brain be Targeted to Treat Type 2 Diabetes?

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Successfully treating type 2 diabetes may involve focusing on brain neurons, rather than simply concentrating on obesity or insulin resistance, according to a study published in the Journal of Clinical Investigation.  

For several years, researchers have known that hyperactivity of a subset of neurons located in the hypothalamus, called AgRP neurons, is common in mice with diabetes. 

“These neurons are playing an outsized role in hyperglycaemia and type 2 diabetes,” said UW Medicine endocrinologist Dr Michael Schwartz, corresponding author of the paper.

To determine if these neurons contribute to elevated blood sugar in diabetic mice, researchers employed a widely used viral genetics approach to make AgRP neurons express tetanus toxin, which prevents the neurons from communicating with other neurons. 

Unexpectedly, this intervention normalised high blood sugar for months, despite having no effect on body weight or food consumption.   

Conventional wisdom is that diabetes, particularly type 2 diabetes, stems from a combination of genetic predisposition and lifestyle factors, including obesity, lack of physical activity and poor diet. This mix of factors leads to insulin resistance or insufficient insulin production.  

Until now, scientists have traditionally thought the brain doesn’t play a role in type 2 diabetes, according to Schwartz. 

The paper challenges this and is a “departure from the conventional wisdom of what causes diabetes,” he said. 

The new findings align with studies published by the same scientists showing that injection of a peptide called FGF1 directly into the brain also causes diabetes remission in mice. This effect was subsequently shown to involve sustained inhibition of AgRP neurons.

Together, the data suggest that, while these neurons are important for controlling blood sugar in diabetes, they don’t play a major role in causing obesity in these mice, the researchers noted in their report.  

In other words, targeting these neurons may not reverse obesity, even as it causes diabetes to go into remission, Schwartz explained. 

More research is needed on how to regulate activity in these neurons, and how they become hyperactive in the first place, he said. Once these questions are answered, Schwartz said that a therapeutic approach might then be developed to calm them down. 

This approach could represent a shift in how clinicians understand and treat this chronic disease, Schwartz said.  He noted, for instance, that semaglutide and other new drugs used to treat type 2 diabetes are also able to inhibit AgRP neurons.  

The extent to which this effect contributes to the antidiabetic action of these drugs is unknown. Further research might help scientists to better understand the role of AgRP neurons in how the body normally controls blood sugar, and to ultimately translate these findings into human clinical trials, he added.  

Source: University of Washington School of Medicine/UW Medicine

Categories : Implants and Prostheses NeurologyTags :

New Auditory Brainstem Implant Shows Early Promise

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A new study co-led by Mass General Brigham researchers points to a promising new type of auditory brainstem implant (ABI) that could benefit people who are deaf due to Neurofibromatosis type 2 (NF2) and other severe inner ear abnormalities that prevent them from receiving cochlear implants. With further tests and trials, researchers hope it will provide a more effective treatment alternative than what is currently used.

In the new research, published in Nature Biomedical Engineering, scientists at Mass Eye and Ear, a member of the Mass General Brigham healthcare system, collaborated with scientists at the École Polytechnique Fédérale de Lausanne (EPFL) in Geneva, Switzerland, to report on a new class of soft, flexible ABIs that were designed to address the limitations of those currently used. These implants bypass damaged auditory structures and directly stimulate the brainstem’s sound-processing region to restore auditory function.

The new ABI was borne out of a decade-long collaboration between Mass Eye and Ear and EPFL scientists. It features an elastic, multilayer construct that includes ultra-thin platinum electrodes and silicone, a novel design that allows it to conform closely to the brainstem’s curved surface.

Conventional ABIs that are sometimes used in patients with NF2 rely on stiff electrodes that struggle to conform to the curved surface of the cochlear nucleus in the brainstem. That limits their effectiveness to modest benefits, typically providing only basic sound awareness to aid lip reading. The design can also cause side effects like discomfort that discourages long-term use.

The novel, soft electrode design was developed using advanced thin-film processing techniques, allowing for closer contact and more precise stimulation. In preclinical tests conducted in Switzerland, two macaques received the implants and underwent several months of behavioural testing. Results showed the animals could consistently distinguish between different patterns of stimulation – which indicated high-resolution auditory perception, a promising sign for eventual human use.

“While cochlear implants are life-changing for many, there remains a group of patients for whom current technology falls short,” said study co-senior author Daniel J. Lee, MD, FACS, Ansin Foundation Chair in Otolaryngology at Mass Eye and Ear. “Our research lays the groundwork for a future auditory brainstem implant that could improve hearing outcomes and reduce side effects in patients who are deaf and do not benefit from the cochlear implant.”

Source: Mass Eye and Ear

Categories : NeurologyTags :

‘Sweet Spot’ for Focused Ultrasound Provides Relief from Essential Tremor

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A surgical lesion site is highlighted in orange following MR-guided focused ultrasound treatment. Structural brain connections associated with optimal tremor response or side effects, as identified in the present study, are depicted in various colors. The background features an ultra-high resolution MRI image acquired at Massachusetts General Hospital. Image courtesy of Andreas Horn, Mass General Brigham.

Essential tremor, a common neurological movement disorder, causes uncontrollable shaking, most often in the hands, but it can also occur in the arms, legs, head, voice, or torso. Essential tremor impacts an estimated 1% of the worldwide population and around 5% of people over 60.

Investigators from Mass General Brigham identified a specific subregion of the brain’s thalamus that, when included during magnetic resonance-guided focused ultrasound (MRgFUS) treatment, can result in optimal and significant tremor improvements while reducing side effects. Their results are published in Science Advances.

“This one-time, noninvasive treatment can have immediate, long-lasting and lifechanging effects for patients and was pioneered here at Brigham and Women’s Hospital 30 years ago,” said co-senior author G. Rees Cosgrove, MD, FRCSC, director of functional neurosurgery at Brigham and Women’s Hospital. “The results of this study will help make the procedure even more safe and effective than it already is and will help other centres around the world improve their outcomes.”

MRgFUS treatment of essential tremor creates a small, permanent lesion in a specific nucleus in the thalamus that is thought to be part of the brain circuit mediating the disorder and disrupts the tremor-causing activity. The research team analysed data from 351 thalamotomy patients that were treated across three international hospitals, the largest cohort assessed to date, to identify the optimal location for this procedure and better understand its impacts on clinical improvements and side effects.

The study identified a set of optimal sites and brain connections to target, as well as locations and connections to avoid that lead to side effects. The team then tested whether this ‘sweet spot’ could be used as a model to predict the outcomes in a cohort of patients treated with the same procedure at another centre, which proved true. The more the ‘sweet spot’ was lesioned, the better the outcome was in all patients’ one-year, post-procedure comparison data. According to the researchers, when thalamotomy patients have good tremor control at one year, it is typically sustained over multiple years.

“Seeing how this procedure can make such a huge impact on patients’ lives is what motivated me to pursue this research,” said lead author Melissa Chua, MD, a senior resident in the Brigham’s Department of Neurosurgery. “It is very exciting to have such robust validation and to be moving toward this treatment becoming even more precise and personalized in the future.”

Next, the team plans to further analyse patient data for a more detailed picture of the evolution of this technology and how patient outcomes have improved, to fully understand the parameters that go into achieving long-term tremor control and minimise side effects.

“It is incredible when you can provide a patient with relief from these tremors,” Cosgrove said. “It is like a gift when patients who have not been able to sing, speak in public, write, or even drink from a cup for years can once again do so – we see it in case after case.”

Source: Mass General Brigham

Categories : Cardiovascular Disease NeurologyTags :

Could a Transient Ischaemic Attack Leave Lasting Fatigue?

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A transient ischaemic attack (TIA) is typically defined as a temporary blockage of blood flow to the brain that causes symptoms that go away within a day, but a new study finds that people who have this type of stroke may also have prolonged fatigue lasting up to one year. The study is published in Neurology®, the medical journal of the American Academy of Neurology (AAN).

The study does not prove that TIAs, also known as mini-strokes, cause lasting fatigue; it only shows an association. “People with a transient ischaemic attack can have symptoms such as face drooping, arm weakness or slurred speech and these resolve within a day,” said study author Boris Modrau, MD, PhD, of Aalborg University Hospital in Denmark. “However, some have reported continued challenges including reduced quality of life, thinking problems, depression, anxiety and fatigue. Our study found that for some people, fatigue was a common symptom that lasted up to one year after the transient ischaemic attack.”

The study involved 354 people with an average age of 70 who had a mini-stroke. They were followed for a year.

Participants completed questionnaires about their level of fatigue within the first two weeks of the mini-stroke and again at three, six, and 12 months later. One questionnaire looked at five different types of fatigue, including overall tiredness, physical tiredness, reduced activity, reduced motivation and mental fatigue. Scores ranged from four to 20 with higher scores indicating more fatigue. Participants had an average score of 12.3 at the start of the study. At three months, the average score decreased slightly to 11.9, at six months to 11.4 and at twelve months to 11.1.

Researchers looked at how many participants experienced fatigue as defined as a score of 12 or higher. Of the participants, 61% experienced fatigue two weeks after the mini-stroke and 54% experienced fatigue at each of the three other testing time periods at three, six and 12 months.

Participants also had brain scans. Researchers found that the presence of a blot clot on a scan was equal between people with long term fatigue and those without it, so this did not explain the reason for the level of fatigue.

Researchers did find that previous anxiety or depression was twice as common in those participants who reported lasting fatigue.

“Long-term fatigue was common in our group of study participants, and we found if people experience fatigue within two weeks after leaving the hospital, it is likely they will continue to have fatigue for up to a year,” said Modrau. “For future studies, people diagnosed with a transient ischaemic attack should be followed in the weeks and months that follow to be assessed for lingering fatigue. This could help us better understand who might struggle with fatigue long-term and require further care.”

A limitation of the study was that while participants were asked to complete the questionnaires themselves, it is possible some responses may have been completed with assistance from relatives or caretakers and this may have influenced responses, including those around fatigue.

Source: American Academy of Neurology

Categories : NeurologyTags :

Under Different Anaesthetics, Same Result: Unconsciousness by Shifting Brainwave Phase

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MIT study finds that an easily measurable brain wave shift may be a universal marker of unconsciousness under anaesthesia

Photo by Anna Shvets on Pexels

At the level of molecules and cells, ketamine and dexmedetomidine work very differently, but in the operating room, they do the same exact thing: anaesthetise the patient. By demonstrating how these distinct drugs achieve the same result, a new study in animals by neuroscientists at The Picower Institute for Learning and Memory at MIT identifies a potential signature of unconsciousness that is readily measurable to improve anaesthesiology care.

What the two drugs have in common, the researchers discovered, is the way they push around brain waves, which are produced by the collective electrical activity of neurons. When brain waves are in phase, meaning the peaks and valleys of the waves are aligned, local groups of neurons in the brain’s cortex can share information to produce conscious cognitive functions such as attention, perception and reasoning, said Picower Professor Earl K. Miller, senior author of the new study in Cell Reports. When brain waves fall out of phase, local communications, and therefore functions, fall apart, producing unconsciousness.

The finding, led by graduate student Alexandra Bardon, not only adds to scientists’ understanding of the dividing line between consciousness and unconsciousness, Miller said, but also could provide a common new measure for anesthesiologists who use a variety of different anesthetics to maintain patients on the proper side of that line during surgery.

“If you look at the way phase is shifted in our recordings, you can barely tell which drug it was,” said Miller, a faculty member in The Picower Institute and MIT’s Department of Brain and Cognitive Sciences. “That’s valuable for medical practice.  Plus if unconsciousness has a universal signature, it could also reveal the mechanisms that generate consciousness.”

A figure from the paper summarises the main findings. Under either ketamine or dexmedetomidine general anaesthesia, brain waves become shifted out of phase within a hemisphere and more into phase across hemispheres.

If more anesthetic drugs are also shown to affect phase in the same way, then anaesthesiologists might be able to use brain wave phase alignment as a reliable marker of unconsciousness as they titrate doses of anesthetic drugs, Miller said, regardless of which particular mix of drugs they are using. That insight could aid efforts to build closed-loop systems that can aid anaesthesiologists by constantly adjusting drug dose based on brain wave measurements of the patient’s unconsciousness.

Miller has been collaborating with study co-author Emery N. Brown, an anaesthesiologist and Professor of Computational Neuroscience and Medical Engineering, on building such a system. In a recent clinical trial with colleagues in Japan, Brown demonstrated that monitoring brain wave power signals using EEG enabled an anaesthesiologist to use much less sevoflurane during surgery with young children. The reduced doses proved safe and were associated with many improved clinical outcomes, including a reduced incidence of post-operative delirium.

Phase findings

Neuroscientists studying anaesthesia have rarely paid attention to phase, but in the new study, Bardon, Brown and Miller’s team made a point of it as they anaesthetised two animals.

After the animals lost consciousness, the measurements indicated a substantial increase in “phase locking,” especially at low frequencies. Phase locking means that the relative differences in phase remained more stable. But what caught the researchers’ attention were the differences that became locked in: Within each hemisphere, regardless of which anesthetic they used, brain wave phase became misaligned between the dorsolateral and ventrolateral regions of the prefrontal cortex.

Surprisingly, brain wave phase across hemispheres became more aligned, not less. But Miller notes that case is still a big shift from the conscious state, in which brain hemispheres are typically not aligned well, so the finding is a further indication that major changes of phase alignment, albeit in different ways at different distances, are a correlate of unconsciousness compared to wakefulness.

“The increase in interhemispheric alignment of activity by anesthetics seems to reverse the pattern observed in the awake, cognitively engaged brain,” the Bardon and Miller team wrote in Cell Reports.

Determined by distance

Distance proved to be a major factor in determining the change in phase alignment. Even across the 2.5 millimetres of a single electrode array, low-frequency waves moved 20-30 degrees out of alignment. Across the 20 or so millimetres between arrays in the upper (dorsolateral) and lower (ventrolateral) regions within a hemisphere, that would mean a roughly 180-degree shift in phase alignment, which is a complete offset of the waves.

The dependence on distance is consistent with the idea of waves traveling across the cortex, Miller said. Indeed in a 2022 study, Miller and Brown’s labs showed that the anaesthetic propofol induced a powerful low-frequency traveling wave that swept straight across the cortex, overwhelming higher-frequency straight and rotating waves.

The new results raise many opportunities for follow-up studies, Miller said. Does propofol also produce this signature of changed phase alignment? What role do travelling waves play in the phenomenon? And given that sleep is also characterised by increased power in slow wave frequencies, but is definitely not the same state as anaesthesia-induced unconsciousness, could phase alignment explain the difference?

Source: Picower Institute

Categories : Cancer NeurologyTags :

CAR-T Cell Therapy Causes ‘Brain Fog,’ Study Shows

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Killer T cells about to destroy a cancer cell. Credit: NIH

After treatment with CAR-T cells, immune cells engineered to attack cancer, patients sometimes tell their doctors they feel like they have “brain fog,” or forgetfulness and difficulty concentrating.

A new Stanford Medicine-led study shows that CAR-T cell therapy causes mild cognitive impairments, independent of other cancer treatments, and that this happens via the same cellular mechanism as cognitive impairment from two other causes: chemotherapy and respiratory infections such as flu and COVID-19. The study, conducted mostly in mice, which was published in Cell, also identifies strategies for reversing the problem.

Medications that ameliorate brain fog will enable better recovery from cancer immunotherapies, the researchers said.

“CAR-T cell therapy is enormously promising,” said senior author, Michelle Monje, MD, PhD, professor in paediatric neuro-oncology. “We need to understand all its possible long-term effects, including this newly recognised syndrome of immunotherapy-related cognitive impairment, so we can develop therapeutic approaches to fix it.”

The study’s lead authors are Anna Geraghty, PhD, senior staff scientist in the Monje lab, and MD/PhD student Lehi Acosta-Alvarez.

Cognitive impairment after CAR-T cell therapy is typically mild; patients are not developing dementia, for instance. But it is frustrating and may not resolve on its own, Monje said. In mice, her team reversed the impairment using compounds similar to existing medications or medications in clinical development – meaning a treatment could be available relatively quickly, she said.

“We’re deeply interested in how cancer therapies affect cognition because it affects patients’ quality of life,” Monje said. “And this is especially important for kids because their brains are still developing.”

Investigating brain fog

CAR-T cell therapy was approved in the US for acute lymphoblastic leukaemia in 2017. The treatment involves removing some of the patient’s own immune cells, known as T cells, and engineering them to attack targets on cancer cells. The modified T cells are returned to the patient’s body, where they recognise and destroy cancer.

In addition to leukaemia, CAR-T cells are now used to treat other blood cancers, including multiple myeloma and some kinds of lymphoma, and they are being tested in clinical trials for various solid tumours. Monje and her colleagues have an ongoing trial of CAR-T cells for deadly brain stem and spinal cord tumours in children, which is beginning to show success.

Although patients report brain fog after CAR-T cell therapy, studies to measure how much cognitive impairment the therapy causes are only just emerging.

The research team wanted to get a comprehensive understanding of the situations in which CAR-T cell therapy might cause cognitive impairment. They studied mice that had tumours induced in the brain, blood, skin and bone. The researchers wanted to understand the influence on cognition of CAR-T cell treatment in combination with the tumours’ location (originating in, spreading to or staying outside the brain), as well as the degree to which the engineered cells evoked additional, accompanying immune responses. Before and after CAR-T cell treatment, the researchers used standard cognitive tests on the mice, measuring how mice responded to a novel object and navigated a simple maze.

CAR-T therapy caused mild cognitive impairment in mice with cancers originating in, metastasizing to and located completely outside the brain. The only mice tested that did not develop cognitive impairment after CAR-T treatment were those that had bone cancer that causes minimal additional inflammation beyond the cancer-fighting activity of the CAR-T cells.

“This is the first study to demonstrate that immunotherapy on its own is sufficient to cause lasting cognitive symptoms,” Monje said. “It’s also the first paper to uncover the mechanisms. We found the exact same pathophysiology we’ve seen in brain fog syndromes that occur after chemotherapy, radiation, and mild respiratory COVID-19 or influenza.”

The researchers demonstrated that the brain’s immune cells, called microglia, are key players in the problem. First, the microglia become activated by the body’s immune response. The activated, “annoyed” microglia produce inflammatory immune molecules known as cytokines and chemokines, which in turn have widespread effects throughout the brain. They are particularly harmful for oligodendrocytes, the brain cells responsible for making myelin, the fatty substance that insulates nerve fibres and helps nerves transmit signals more efficiently. Reduction in the nerves’ insulation translates into cognitive impairment.

Examining tissue samples

The scientists also analysed samples of brain tissue from human subjects who participated in the team’s ongoing clinical trial of CAR-T cells for spinal cord and brain stem tumours. Using post-mortem tissue samples, the researchers confirmed that microglia and oligodendrocytes appear dysregulated in the same way the team had observed in mice after CAR-T therapy.

In mice, the research team tested strategies to resolve the cognitive problems. They gave a compound that depleted microglia in the brains of the mice for a two-week period. After that transient depletion, the microglia  returned in the brain in a normal, non-reactive state. The mice were no longer cognitively impaired.

The researchers also gave the mice a medication that enters the brain and interferes with signals from damaging chemokines, blocking a specific receptor for these molecules.

“That alone rescued cognition,” Monje said, adding that the researchers are now exploring how to safely translate the two strategies – transiently depleting microglia or interrupting chemokine signals – in people who have had CAR-T cell therapy.

“This research further illustrates that there is a unifying principle underpinning brain fog syndromes,” said Monje, a member of the Stanford Cancer Institute. “And this particular study is so exciting because not only have we identified the cells central to this pathophysiology, we’ve found a molecular target we can investigate to treat it.”

Source: Stanford Medicine

Categories : Ageing NeurologyTags :

Analysis of Pulse Rate can Predict Faster Cognitive Decline in Older Adults

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Photo by Matteo Vistocco on Unsplash

Healthy hearts are adaptable, and heartbeats exhibit complex variation as they adjust to tiny changes in the body and environment. Mass General Brigham researchers have applied a new way to measure the complexity of pulse rates, using data collected through wearable pulse oximetry devices. The new method, published in the Journal of the American Heart Association, provides a more detailed peek into heart health than traditional measures, uncovering a link between reduced complexity and future cognitive decline.

“Heart rate complexity is a hallmark of healthy physiology,” said senior author Peng Li, PhD, of the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital (MGH) and the Division of Sleep and Circadian Disorders at Brigham and Women’s Hospital (BWH). “Our hearts must balance between spontaneity and adaptability, incorporating internal needs and external stressors.”

The study used data from 503 participants (average age 82, 76% women) in the Rush Memory and Aging Project. The researchers analysed overnight pulse rate measurements – collected by a fingertip pulse oximetry device known as the Itamar WatchPAT 300 device – and comprehensive measures of cognitive functions, collected around the same time as the pulse rate measurement and at least one annual follow-up visit up to 4.5 years later.

The team found that people with greater complexity in their heartbeats at baseline tend to experience slower cognitive decline over time. They determined that the conventional measures of heart rate variability did not predict this effect, indicating their measure was more sensitive in capturing heart functions predictive of cognitive decline.

The researchers plan to investigate whether pulse rate complexity can predict development of dementia, which would make it useful for identifying people at an early stage who might benefit from therapeutic interventions.

“The findings underscore the usefulness of our approach as a noninvasive measure for how flexible the heart is in responding to nervous system cues,” said lead author Chenlu Gao, PhD, also in the Department of Anesthesia, Critical Care and Pain Medicine at MGH. “It is suitable for future studies aimed at understanding the interplay between heart health and cognitive aging.”

Source: Mass General Brigham