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Using cutting-edge imaging technology, researchers at Massachusetts General Hospital (MGH) have shown that the brains of young men with autism spectrum disorder (ASD) have low levels of a protein that appears to play a role in inflammation and metabolism. This surprising discovery, which published online today in the journal Molecular Psychiatry provides an important new insight into the possible origins of ASD, which affects one in 59 children.

ASD is a developmental disorder that emerges in early childhood and is characterized by difficulty communicating and interacting with others. While the cause is unknown, growing evidence has linked ASD to inflammation of brain tissue, or neuroinflammation. One sign of neuroinflammation is elevated levels of a substance called translocator protein (TSPO), which can be measured and located in the brain using positron-emission tomography (PET) and anatomical magnetic resonance imaging (MRI). The MGH study, led by Nicole Zurcher, PhD, an investigator in MGH's Athinoula A. Martinos Center for Biomedical Imaging, was the first to use a new generation of PET "tracers," which more accurately detect TSPO, to examine the brains of people with ASD.

In the study, Zurcher and her colleagues scanned the brains of 15 young adult males (average age, 24) with ASD. The group included both high- and low-functioning subjects with varying degrees of intellectual abilities. For comparison, Zurcher's team scanned the brains of 18 healthy control subjects who were similar in age. The investigators hypothesized that the scans would show increased levels, or expression, of TSPO in subjects who have ASD.

"To our surprise, that's not what we saw," says Zurcher. Instead, the scans showed that the brains of males with ASD had lower levels of TSPO than those of the healthy subjects. In fact, the men with the most severe symptoms of ASD tended to have the lowest expression of TSPO. When the tests were repeated several months later, the pattern persisted. The brain regions found to have low expression of TSPO have previously been linked to ASD in earlier studies, and are believed to govern social and cognitive capacities such as processing of emotions, interpreting facial expressions, empathy, and relating to others. "We know these brain regions are involved in autism," says Zurcher.

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To understand this unexpected finding, Zurcher notes that TSPO does more than serve as a marker of inflammation. "It has multiple complex roles," she says, and some actually promote brain health. For example, adequate TSPO is necessary for normal functioning of mitochondria, which are the "power houses" in cells that produce energy. Earlier research has linked malfunctioning mitochondria in brain cells to ASD.

Zurcher and her colleagues next plan to study brains from deceased donors with the goal of determining which brain cells in people with ASD might experience mitochondrial dysfunction, which she says may well be occurring alongside neuroinflammation and other mechanisms to cause ASD.

Our study has generated new hypotheses that now need to be investigated. There's more work to be done."

Nicole Zurcher, PhD, investigator, MGH's Athinoula A. Martinos Center for Biomedical Imaging

Source:

Massachusetts General Hospital

Journal reference:

Zürcher, N.R., et al. (2020) [11C]PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder. Molecular Psychiatry. doi.org/10.1038/s41380-020-0682-z.

A new simple blood test for brain tumors that could be used by GPs in primary care is being developed thanks to funding of nearly £500,000 by Cancer Research UK. Around 60,000 patients in the UK are living with a brain tumor but only 20 per cent of patients are still alive five years after diagnosis, partly because they present late with large inoperable tumors.

The University of Bristol-led research project to develop an affordable, point of care blood test to diagnose brain tumors earlier using fluorescent carbon dots and nanophotonics will be headed by Dr. Kathreena Kurian, Associate Professor in Brain Tumour Research and Dr. Sabine Hauert, Senior Lecturer in Robotics in collaboration with co-investigators: Professors Carmen Galan and Richard Martin at the University of Bristol; Dr. Neciah Dorh at FluoretiQ Limited and Dr. Helen Bulbeck at Brainstrust.

The cross-disciplinary research project brings together medical practitioners, along with experts in population health, nanoparticle engineering and detection, as well as computational modeling.

Dr. Kathreena Kurian, Head of the Brain Tumour Research Centre at the University of Bristol, said:

A simple blood test carried out by GPs would help decision-making and early diagnosis. This would revolutionize care by speeding up diagnosis, reducing costs to the NHS, anxiety of unnecessary scans and reducing the number of patients presenting with inoperable large brain tumors.

Additionally, this test could be used as an early monitor of brain tumor recurrence. Our work will be followed by a multicentre cohort biomarker study to determine the effectiveness of the test in a real-world setting."

Dr. Sabine Hauert from the Department of Engineering Mathematics and Bristol Robotics Laboratory (BRL), added: "Nanoparticles have shown promise in early detection of cancer by fluorescent labeling of very low levels of biomarkers in blood samples and other fluids."

Dr. Alexis Webb, Cancer Research UK's senior early detection funding manager, said:

At the moment the number of people who survive after a brain tumor diagnosis remains low and little has changed in over a generation. We're proud to support this innovative project and funding brain tumor research remains a priority for the charity. We need better techniques to diagnose brain tumors earlier, when more treatment options are available, to secure a future for more people affected by the disease."

Professor Carmen Galan, Professor of Organic and Biological Chemistry in the School of Chemistry, who has developed the fluorescent carbon-based nanomaterials that form the basis for the project, explained: "The fluorescent nanoprobes are produced by low-cost renewable routes and we have shown that we can decorate them with different biomolecules to target specific biomarkers in physiological conditions, which is really exciting."

Dr. Neciah Dorh, CEO of FluoretiQ Limited, stated:

As a diagnostics company, we are passionate about creating technology that can improve people's lives and we see this project as natural extension of the work that we are currently doing in infectious disease."

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In the UK in 2013, 38 percent of brain tumor patients visited their GP five times or more before being referred for diagnosis by imaging MRI/CT scan and neurosurgical biopsy, because the symptoms such as headache are non-specific, so there is an urgent need to develop new tests for brain tumors to help GPs diagnose brain tumors earlier.

There is a pressing need for the discovery of new blood biomarkers for brain cancer and state-of-the-art technology that allows for its sensitive detection. The aims of the research project are:

  • discover novel biomarkers, in addition to known markers such as Glial fibrillary acidic protein (GFAP), which will be used as a baseline;
  • implement a computational model to predict biomarker levels in blood;
  • develop a fluorescent nanoparticle that can label this marker in blood;
  • work with Bristol-based start-up FluoretiQ towards an affordable near patient testing solution.

Glioblastoma is the most common type of malignant brain tumor among adults and it is usually very aggressive, which means it can grow fast and spread quickly. It is characterized by abnormal blood vessels following a leaky blood-brain barrier (BBB). GFAP is unique to the brain and not present in blood that circulates throughout the body. Antibodies in GFAP are used to diagnose gliomas in tissue samples. There is evidence that GFAP crosses the leaky BBB and is an early non-specific peripheral blood biomarker which predates the clinical diagnosis of glioblastoma.

However, GFAP levels are too low for routine detection by routine protein detection tests such as ELISA. The research team has already identified other novel potential protein biomarkers of brain tumours using the epidemiological method, Mendelian Randomization, which may be present in low levels in the blood.

Fluorescent carbon dots (FCDs), also known as nanoparticles, are cheap and easy to create using a three-minute synthesis. FCDs can be readily attached to ligands such as antibodies targeting specific protein markers. FCDs labeling biomarkers can then be detected using nanophotonic technology, which has been developed by FluoretiQ, for rapid, sensitive, and low-cost diagnosis. Computational modeling will then be used to predict tumor size given biomarker availability in blood and establish the theoretical limits of the detection.

Source:

University of Bristol

The addition of dietary L-serine, a naturally occurring amino acid necessary for formation of proteins and nerve cells, delayed signs of amyotrophic lateral sclerosis (ALS) in an animal study.

The research also represents a significant advance in animal modeling of ALS, a debilitating neurodegenerative disease, said David A. Davis, Ph.D., lead author and research assistant professor of neurology and associate director of the Brain Endowment Bank at the University of Miami Miller School of Medicine.

The new research protocol using vervets appears more analogous to how ALS develops in humans, Dr. Davis said, compared to historic models using rodents. When he and colleagues gave the vervets a toxin produced by blue-green algae known as β-N-methylamino-L-alanine or BMAA, they developed pathology that closely resembles how ALS affects the spinal cords in humans.

When a group of these animals were fed L-serine together with BMAA for 140 days, the strategy was protective – the vervets showed significantly reduced signs of protein inclusions in spinal cord neurons and a decrease in pro-inflammatory microglia. The results were published on Thursday, February 20 at 5 a.m. EST in the prestigious Journal of Neuropathology & Experimental Neurology.

"The big message is that dietary exposure to this cyanobacterial toxin triggers ALS-type pathology, and if you include L-serine in the diet, it could slow the progression of these pathological changes," Dr. Davis said.

"I was surprised at how close the model mirrored ALS in humans," he added. Beyond looking at changes in the brain, "When we looked at the spinal cord, that was really surprising." The investigators observed changes specific to ALS seen in patients, including presence of intracellular occlusion such as TDP-43 and other protein aggregates.

Walter G. Bradley D.M., F.R.C.P., founder of the ALS Clinical and Research Center at the University of Miami Miller School of Medicine, said: "ALS is a progressive neurological disease, also known as Lou Gehrig's disease, causing progressive limb paralysis and respiratory failure. There is a great unmet need for effective therapies in this disease. After clinical trials of more than 30 potential drugs to treat ALS, we still have only two that slow the disease progression."

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ALS can rapidly progress in some people, leading to death in 6 months to 2 years after diagnosis. For this reason, it is difficult to enroll people in clinical trials, a reality that supports development of a corresponding animal model, Dr. Davis said.

In addition, prevention remains essential. "This is a pre-clinical model, which is really the most important type of model, because once people have full-blown disease, it's hard to reverse or slow its progression," he added.

The research builds on earlier findings from Dr. Davis and colleagues in a 2016 study that demonstrated cyanotoxin BMAA can cause changes in the brain that resemble Alzheimer's disease in humans, including neurofibrillary tangles and amyloid deposits.

Even with the promise of L-serine, the researchers note there is a bigger picture to their new ALS animal model. "Other drugs can also be tested, making this very valuable for clinical affirmation," Davis said.

The research also has implications for Florida, as BMAA comes from harmful blue-green algae blooms, which have become more common in the summer months in Florida.

According to Larry Brand, Ph.D., professor of marine biology at the Rosenstiel School at the University of Miami, "We have found that the BMAA from these blooms has biomagnified to high concentrations in South Florida aquatic food chains, thus our seafood."

We are very curious about how BMAA affects individuals in South Florida. That's our next step."

Dr. David A. Davis, Ph.D., lead author

Future research could attempt to answer multiple questions, including: How common is BMAA in local seafood? What are the risks of exposure through exposure to aerosolized cyanotoxins? Is there a specific group of people who are more vulnerable from this exposure to developing diseases like Alzheimer's and ALS?

The current research would not have been possible, Dr. Davis said, without interdisciplinary collaboration both inside and outside the University of Miami. Another essential factor is the "very unique research environment" in the UM Department of Neurology. For example, the Brain Endowment Bank allows Miller School researchers access to other investigators and to essential research material.

Source:

University of Miami Miller School of Medicine

Journal reference:

Davis, D.A., et al. (2020) L-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND. Journal of Neuropathology & Experimental Neurology. doi.org/10.1093/jnen/nlaa002.