Tag Archives: Brain

The blood-brain barrier has been non-invasively opened in a patient for the first time. Scientists used focused ultrasound to enable temporary and targeted opening of the blood-brain barrier (BBB).

Opening the blood-brain barrier in a localized region to deliver chemotherapy to a tumor is a predicate for utilizing focused ultrasound for the delivery of other drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurological conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric diseases.

The team infused the chemotherapy agent doxorubicin, along with tiny gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate, loosening the tight junctions of the cells comprising the blood-brain barrier and allowing high concentrations of the chemotherapy to enter targeted tissues.

While the current trial is a first-in-human achievement, Dr. Kullervo Hynynen, senior scientist at the Sunnybrook Research Institute, has been performing similar pre-clinical studies for about a decade. His research has shown that the combination of focused ultrasound and microbubbles may not only enable drug delivery, but might also stimulate the brain’s natural responses to fight disease. For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s and improves cognitive function.

Source: Focused Ultrasound Foundation

Researchers are proposing a new way of understanding Amyotrophic Lateral Sclerosis (ALS), the devastating and incurable neurological disease. Their findings, published in the journal Neuron, could be a major milestone on the path to a treatment for both ALS and dementia.

By delving into a previously overlooked corner of ALS research, the team discovered a new way in which the disease kills nerve cells.

Many cases of ALS are sparked by a toxic build-up of certain proteins, which cause neurons in the brain and spinal cord to die. Over the last decade, mutations that cause ALS have been found in a growing number of genes that encode RNA-binding proteins. The protein they create commonly builds up inside the diseased brain and spinal cords in ALS patients. Until now, scientists haven’t thought this build-up was important to the disease process because it looked different from the types of protein accumulations — such as tau, amyloid and alpha synuclein — that are clearly toxic and always found in patients with Alzheimer’s, Parkinson’s and some forms of dementia.

The research team decided to take a closer look at these seemingly innocuous protein accumulations. They focused initially on the FUS protein, and discovered that these abnormal clumps could actually be a very important player in causing nerve cell damage and ALS. The research team found that mutations in FUS changed the property of FUS protein so that it tends to form very dense gels that do not easily re-melt and release their cargo appropriately. As a result, it’s unable to deliver the tools necessary for the neurons to stay healthy and do their job.

The next step is for researchers to find ways to prevent the solidification of the gel, or to reverse the hardening process, offering a key to a future drug to treat ALS and frontotemporal dementia — another disease in which the protein is active.

Source: University of Toronto

A study of the brains of mice shows that structural deterioration associated with old age can be prevented by long-term aerobic exercise starting in mid-life, according to a research article published in PLOS Biology. Researchers found that structural changes that make the blood-brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly, so providing a potential explanation for the beneficial effects of exercise on dementia in humans.

Physical activity is already known to ameliorate the cognitive decline and sensorimotor deficits seen in old age in humans as well as in mice. To investigate the impact of long-term physical exercise on the brain changes seen in the aging mice, the researchers provided the animals with a running wheel from 12 months old (equivalent to middle aged in humans) and assessed their brains at 18 months (equivalent to ~60yrs old in humans, when the risk of Alzheimer’s disease is greatly increased). Young and old mice alike ran about two miles per night, and this physical activity improved the ability and motivation of the old mice to engage in the typical spontaneous behaviors that seem to be affected by aging. This exercise significantly reduced age-related pericyte loss in the brain cortex and improved other indicators of dysfunction of the vascular system and blood-brain barrier.

Source: PLOS Biology

Investigators have discovered a mechanism behind the spread of neurofibrillary tangles – one of the two hallmarks of Alzheimer’s disease – through the brains of affected individuals. In a report in the journal Nature Communications, researchers describe finding that a particular version of the tau protein, while extremely rare even in the brains of patients with Alzheimer’s disease, is able to spread from one neuron to another and how that process occurs.

“It has been postulated that tangles – the abnormal accumulation of tau protein that fills neurons in Alzheimer’s disease – can travel from neuron to neuron as the disease progresses, spreading dysfunction through the brain as the disease progresses. But how that happens has been uncertain,” said Bradley Hyman, M.D., Ph.D., director of the Massachusetts General Hospital (MGH) Alzheimer’s Disease Research Center and senior author of the report. “Our current study suggests one mechanism at play is that a unique and rare type of tau has the properties we were looking for – it is released from neurons, taken up by other neurons, transported up and down axons, and then released again.”

The current study revealed that, when brain samples from that mouse model were applied to cultured neurons, only 1 percent of the tau in those samples was taken up by the neurons. The tau proteins that were taken up were high molecular weight – meaning that a number of smaller proteins are bound together into a larger molecule – soluble, and studded with a large number of phosphate molecules, a known characteristic of the tau in Alzheimer’s-associated tangles. Similar results were seen in experiments using brain samples from Alzheimer’s patients, both in cultured neurons and in living mice.

Source: Massachusetts General Hospital

New research could lead to improved methods of detection for early-onset Parkinson’s disease (PD).

Recording the responses of fruit flies (Drosophila melanogaster) to different visual patterns, using methods adapted from the study of vision in humans, scientists investigated the nervous systems of flies with different types of Parkinson’s mutations.

The researchers compared flies carrying mutations associated with early-onset Parkinson’s with ‘normal’ control flies and found increased neuronal activity to stimulation in the former group in ‘young’ flies.

By mapping the visual responses of fruit flies with different Parkinson’s genes, the scientists built a substantial data bank of results. Using this they were able to classify unknown flies as having a Parkinson’s-related mutation with 85 per cent accuracy.

Researchers believe it may be possible to transfer this method back to the clinic where early changes in vision may provide a ‘biomarker’ allowing screening for Parkinson’s before the onset of traditional motor-symptoms. Therefore, profiling human visual responses could prove an accurate and reliable test in diagnosing people with early-onset PD.

This method is also likely to succeed when transferred to human detection of Parkinson’s, as visual profiling in humans has proved accurate in the past in detecting genetic markers. In this study, as more complex light stimulations have been used, a more accurate picture of detecting a wider variety of different genetic markers has been revealed.

Source: University of York

Alzheimer’s disease is characterised by two types of lesions, amyloid plaques and degenerated tau protein. Cholesterol plays an important role in the physiopathology of this disease. Two research teams have shown, in a rodent model, that overexpressing an enzyme that can eliminate excess cholesterol from the brain may have a beneficial action on the tau component of the disease, and completely correct it. This is the first time that a direct relationship has been shown between the tau component of Alzheimer’s disease and cholesterol. This work is published in Human Molecular Genetics.

The first step in this work made it possible to show that injecting a viral vector, AAV-CYP46A1, effectively corrects a mouse model of amyloid pathology of the disease, the APP23 mouse. CYP46A1 thus appears to be a therapeutic target for Alzheimer’s disease.

Conversely, in vivo inhibition of CYP46A1 in the mice, using antisense RNA molecules delivered by an AAV vector administered to the hippocampus, induces an increase in the production of Aß peptides, abnormal tau protein, neuronal death and hippocampal atrophy, leading to memory problems. Together these elements reproduce a phenotype mimicking Alzheimer’s disease.

These results demonstrate the key role of cholesterol in the disease, and confirm the relevance of CYP46A1 as a potential therapeutic target (work published in Brain on 3 July 2015).

Taken together, this work now enables the research team to propose a gene therapy approach for Alzheimer’s disease: intracerebral administration of a vector, AAV-CYP46A1, in patients with early and severe forms (1% of patients, familial forms) for whom there is no available treatment.

Source: Inserm

Alzheimer’s patients frequently suffer from sleep disorders, mostly even before they become forgetful, and it is known that sleep plays a very important role in memory formation. Researchers have now been able to show for the first time how the pathological changes in the brain act on the information-storing processes during sleep. Using animal models, they were able to decode the exact mechanism and alleviate the impairment with medicinal agents. The study was published in Nature Neuroscience.

The sleep slow waves, also known as slow oscillations, which our brain generates at night, have a particular role in consolidating what we have learned and in shifting memories into long-term storage. These waves are formed via a network of nerve cells in the brain’s cortex, and then spread out into other parts of the brain, such as the hippocampus.

The study used mouse models, which form the same protein deposits, known as β-amyloid plaques, that are visible in human patients. The scientists were able to show that these plaques directly impair the slow wave activity. The scientists also succeeded in decoding this defect at the molecular level: correct spread of the waves requires a precise balance to be maintained between the excitation and inhibition of nerve cells. In the Alzheimer models, this balance was disturbed by the protein deposits, so that inhibition was reduced.

The researchers used this knowledge to treat the defect with medication. One group of sleep-inducing drugs, benzodiazepines, is known to boost inhibitory influences in the brain. If the scientists gave small amounts of this sleep medication to the mice (approximately one-tenth of the standard dose), the sleep slow waves were able to spread out correctly again. In subsequent behavioral experiments, they were able to demonstrate that learning performance had improved as well.

Source: Technical University of Munich

A digital map of the ageing brain could aid the diagnosis of Alzheimer’s disease and other neurodegenerative disorders in older people, a study suggests.

The atlas created using images from MRI scans of older people could aid diagnosis by comparing the patients’ scans with a detailed map of the healthy ageing brain.

Most existing MRI atlases are based on the brains of young and middle-aged people, which don’t reflect the normal changes that take place in the brain as we age, the team says. Researchers at the University of Edinburgh constructed a detailed atlas of the human brain using MRI scans from more than 130 healthy people aged 60 or over.

The team used their atlas to study brain scans taken of normal older subjects and those who had been diagnosed with Alzheimer’s disease. The atlas was able to pinpoint changes in patients’ brain structure that can be an underlying sign of the condition, researchers say.

The study is published in the journal PLOS ONE.

Dr David Alexander Dickie, of The University of Edinburgh’s Brain Research Imaging Centre and SINAPSE, who was first author of the study, said: “We’re absolutely delighted with these preliminary results and that our brain MRI atlases may be used to support earlier diagnoses of diseases such as Alzheimer’s. Earlier diagnoses are currently our strongest defence against these devastating diseases and, while our work is preliminary and ongoing, digital brain atlases are likely to be at the core of this defence.”

Source: University of Edinburgh

Epigenetic modifications control gene expression, but scientists still don’t know if or how they contribute to disease. To address this knowledge gap, the National Institutes of Health launched the Roadmap Epigenomics Project in 2008 to compare epigenomes in healthy and diseased cells.

In the August 17 Nature Neuroscience, two papers from separate but collaborative research groups report on some of the fruits of that effort. Both groups surveyed DNA methylation in hundreds of human AD and control brains and identified several regions where changes in this epigenetic mark correlated with the amount of Alzheimer’s pathology. The results may help flag genes that are turned up or down in AD, and provide insight into pathogenesis, said Philip De Jager at Brigham and Women’s Hospital, Boston, the first author of one of the papers.