Toxic Protein Build-Up In Blood Shines Light On Fatal Brain Disease

A new light-based technique for measuring levels of the toxic protein that causes Huntington’s disease (HD) has been used to demonstrate that the protein builds up gradually in blood cells. Published today (17th) in the Journal of Clinical Investigation, the findings shed light on how the protein causes damage in the brain, and could be useful for monitoring the progression of HD, or testing new drugs aimed at suppressing production of the harmful protein.

HD is a fatal, incurable, genetic neurological disease that usually develops in adulthood and causes abnormal involuntary movements, psychiatric symptoms and dementia. It is caused by a genetic mutation that results in the production of a harmful protein, called mutant huntingtin.

The research team, led by Professor Sarah Tabrizi of the UCL Institute of Neurology, was made up of scientists from UCL, the Novartis Institutes for Biomedical Research and King’s College London. They used a new, ultra-sensitive test to measure how much of the harmful protein and its normal counterpart are found in blood cells from HD patients at different stages of the disease. The test, called TR-FRET, uses pairs of antibodies that stick to huntingtin molecules to absorb and emit light of different colours. This enables very tiny amounts of huntingtin to be detected with great accuracy.

The researchers found that levels of the harmful mutant huntingtin protein built up gradually over the course of the disease, from before the patients show any symptoms onwards. HD causes the brain to shrink more rapidly than normal, as measured using MRI scans. Surprisingly, the amount of mutant protein in white blood cells corresponded to the rate of brain shrinkage. This is the first time a blood test has been able to predict brain shrinkage in a neurodegenerative disease. Levels of the normal huntingtin protein, on the other hand, stayed constant throughout the disease.

The team went on to demonstrate that small fragments of the most toxic part of the protein were slowly building-up in the white blood cells – the first time this has been demonstrated in cells from human HD patients. If a similar process occurs in brain cells such as neurons, this finding may help explain how the damage gradually accumulates, eventually causing symptoms of HD.

This build-up of the mutant protein in the white blood cells of the immune system may also explain previous findings by Professor Tabrizi’s team which showed that the immune system is hyperactive in HD.

“Measuring levels of the mutant protein using TR-FRET is a useful new tool in the fight against HD,” said Professor Tabrizi. “We can now accurately study the most toxic form of the huntingtin protein in easily obtained blood samples from real patients. The fact that mutant huntingtin levels correlate with brain atrophy tells us we’re dealing with something that’s relevant to the process of brain degeneration in HD.”

The new technique could also be an asset for forthcoming clinical trials of ‘gene silencing’ drugs that aim to suppress production of the toxic protein in the brain.

“Gene silencing drugs are very promising, but have significant potential for causing side effects, so we really need to know they’re doing their job of lowering huntingtin levels,” continued Professor Tabrizi. “This TR-FRET technique offers a way of showing that in real human samples, and we hope that it will help speed up the process of developing drugs that work to slow down this terrible disease.”

Is your headache hiding brain tumour?

Have you been paying attention to those bouts of headache that plague you before an important meeting? If you belong to the breed that believes in popping a headache pill to get on with your day, here’s a thought— it may be a brain tumour and not just a simple migraine.

Take the case of Mohammed Basheer*, who was referred to doctors at Fortis Malar Hospital with a prognosis of an ENT problem with an intense one-sided headache. After a scan was taken by curious doctors, who were unable to diagnose the reason behind the headache, they found that there was a tumour in Basheer’s brain. “It had to be removed immediately, otherwise it could have been fatal,” said Dr V Soundappan, senior consultant neurosurgeon at the hospital.

Though only a small fraction of people with headaches have been seen to have neurological problems that caused the pain, Soundappan pointed out that almost every person with a brain problem had headache as a symptom. “There are lots of people who have headaches periodically and self-diagnose believing that it is a migraine. Surely some of them may have tumours or anuerysyms which even general practitioners will not be able to identify,” he added. This is why it might not be such a bad idea to pay a visit to a neurologist to find out whether your headache is ‘benign’ or ‘malignant’.

So what are the differences between a normal headache and one caused by neurological issues? According to Dr Soundappan, watching for variations in the pattern of headaches is the key, “Every person has a different pattern when they have headaches — the severity, duration, interval and so on. Whenever the headaches become irregular and come more often or harder than they normally are, then that warrants neurological care,” he said.

   The other warning signs are when a person wakes up with a severe headache that subsides as soon as they have a spell of vomiting — this is almost always a sign of a brain tumour or increased pressure in the brain.
 “Fever with headaches or waking up with blurry vision, weakness or seizures are all signs of either an aneurysm or even meningitis,” he said. So, before you dismiss your headache the next time it comes calling, stop and consider how bad it is —  you may be able to catch a neurological issue early and nip it in the bud.

Brain-healthy lifestyle may prevent symptoms of Alzheimer's

Alzheimer's disease is the sixth leading cause of death in the U.S., and that figure isn't going down. In fact, as America's older population grows, deaths from Alzheimer's continue to rise, and have increased 66 percent since 2000. If current population trends continue and no cure is found, the actual number of people living with the disease could double every 20 years.

Lifestyle factors, however, can play an important role in protecting your brain as you age. By leading a "brain-healthy" lifestyle, you may even be able to prevent the symptoms of Alzheimer's disease entirely and slow down, or even reverse, the deterioration of aging.

The health of your brain, like the health of your body, depends on many factors. While some factors, such as your genes, are out of your control, many powerful lifestyle factors are within your control. If you are an older adult, or the caretaker of an aging parent or grandparent, a few key factors will help you get and remain "brain healthy," and may help the afflicted person to continue functioning.  They include:

• Exercising regularly
• Eating a healthy diet
• Mental stimulation
• Getting a quality sleep
• Managing stress
• Maintaining an active social life

If you are caring for an aging parent or grandparent, don't neglect your own needs.  Take a break and do something you enjoy. If you are feeling guilty, angry or frustrated, realize that these feelings are normal and that you are not alone. You are not failing as a caregiver by asking others for assistance. So, seek out the support of your family, friends and resources in your community.

Brain-eating amoeba claims 2nd victim in Vietnam

Doctors in Ho Chi Minh City said that a six-year-old boy has become the second person to be killed recently by a rare disease caused by a brain-eating amoeba.

Saigon Tiep Thi newspaper Monday quoted doctors at the HCMC Hospital of Tropical Diseases as saying they found the amoeba Naegleria fowleri, which causes primary amoebic meningoencephalitis, in a sample sent by the Center for Forensic Science.

further information is available yet and the identity of the dead boy is not known.

Dr Phan Van Hieu, director of the center, which is run by the city Health Department, told the newspaper that an investigation has begun.

The results are expected later this week, Hieu told Tuoi Tre newspaper.

Tran Phu Manh Sieu, director of the Preventive Health Department told Thanh Nien that he has yet to receive a report on the case.

Earlier this month the Ministry of Health said that a 27-year-old man was the first ever victim of the disease in Vietnam. He had been hospitalized on July 30 and died three days later.

The man, belonging to the central province of Phu Yen, was suspected of contracting the amoeba when swimming in a lake to catch oysters in a village near his hometown.

Saigon Tiep Thi quoted experts as saying that the two cases proved that the amoeba does pose a threat in Vietnam, but was never detected or mentioned before due to the lack of knowledge and equipment.

The HCMC Hospital of Tropical Diseases had diagnosed the first case only with support from British experts.

Make sure you mind your brain

By Dr. Michael Warren

I think most of you have heard the expression “a mind is a terrible thing to waste.” It was actually a phrase used by a college to encourage donations for student scholarships. But, it is absolutely true as a general statement.

Our brains are one of the most important of our body organs. Its size and complexity is what separates us from lower forms of life. It also is one of the most fragile of our organs, fortunately protected by our skulls, or at least partially protected by our skulls.

The same skulls can damage the brain if external force is applied, as in automobile accidents, for example, so that the skull is fractured and a piece of the broken bone pierces the brain.

Let’s talk a little about two aspects of brain wasting.

The first is brain damage caused by our lifestyles and daily activities. I have discussed motorcycle riding without a helmet and angered enough people about that, so I won’t say much more about it.

Let me really go out on a limb and anger everyone else, especially Texans. Let me talk about an activity that is becoming more and more understood as a frequent cause of brain injury. An activity that is so ingrained in our daily lives that to even read these words will cause some to burn this paper.

You got it — football.

We are learning more and more about seemingly harmless trauma that can cause significant brain damage, and for it to happen again and again is just asking for trouble.

Besides concussions, do you want to talk about knee, ankle, shoulder, arms, legs and spine injuries? Same song, second verse.

I admit I have a personal interest in this. His name is Daniel, and he is my grandson. He is about to be 12 years old and he competes on the gridiron with others his age. It is amazing how 11-year-old boys can be so different in size and shape.

He is not the biggest on the team, but he is the toughest. His coach is an ex-NFL player. His father is the assistant coach. His mother and I are scared every time he tackles someone when he is a linebacker and is tackled by someone when he plays offensive backfield.

Every time I bring up the subject of perhaps reducing his football experience, I become the Grinch who stole football. He and his father explain to me, usually in very nice terms, to mind my own business. They say I forget when I was young. Sometimes they tell me it is too bad I was born before football was invented.

That brings us to the second type of brain wasting. Right again. I am talking about senile dementia or Alzheimer’s. There is increasing research in the prevention and treatment for this age-old problem of old age.

Once you or some member of your family begins to notice changes in your memory, you should take action to get medical help. There is no cure yet, but there are ways to slow down or otherwise deal with the disease.

Keep your brain working. My wife plays bridge and she is sure it is helping her memory. I believe she is right. I have noticed that I have difficulty remembering what football games are on which night. I need to do something about that.

Dr. Michael M. Warren is Ashbel Smith professor of surgery at University of Texas Medical Branch Division of Urology. Write him at michael.warren(at)galvnews.com. 

Studies: Alzheimer's drug may stabilize brain plaque

An experimental drug that failed to stop mental decline in Alzheimer's patients also signaled potential benefit that suggests it might help if given earlier, fuller results of two major studies show.

Some patients on the drug had stable levels of brain plaque and less evidence of nerve damage compared with others who were given a dummy treatment, researchers reported.

The drug is called bapineuzumab, made by Pfizer Inc. and Johnson & Johnson. The new results suggest it might work if given sooner, before so much damage and memory loss have occurred that it might not be possible to reverse, experts say.

"We're very disappointed that we were not able to come up with a treatment to provide to our dementia patients in the near term," said Dr. Reisa Sperling, director of the Alzheimer's center at Brigham and Women's Hospital in Boston and leader of one of the studies.

But brain imaging and spinal fluid tests are "very encouraging" and suggest the drug was "doing something to the biology of the disease."

"We've got a path forward" now to test it in people with mild mental impairment or those who show plaque on brain imaging but have not yet developed symptoms of dementia, Sperling said. Of people with mild cognitive impairment, about 15 to 20 percent a year will develop Alzheimer's disease.

About 35 million people worldwide have dementia, and Alzheimer's is the most common type. In the U.S., about 5 million have Alzheimer's. Current medicines such as Aricept and Namenda just temporarily ease symptoms. There is no known cure.

This year researchers had been hopeful of major progress in treating the disease, but study after study has proved disappointing, including results reported earlier on bapineuzumab. The drug failed to slow mental decline or improve activities of daily living for patients with mild to moderate Alzheimer's in two studies in the United States and Canada.

Bapineuzumab is designed to attach to and help clear amyloid, the stuff that makes up the sticky plaque that clogs patients' brains, harming nerve cells and impairing memory and thought. Doctors don't know whether amyloid is a cause or just a symptom of Alzheimer's, but many companies are testing drugs to try to remove it.

Sperling's study involved people with a gene that raises the risk of developing the disease. Dr. Stephen Salloway, a neurologist at Brown Medical School in Providence, R.I., led the other study of people without the gene. Both researchers have consulted for the companies that make the drug and presented results last week at a neurology conference in Stockholm.

Brain imaging on a subset of patients in Sperling's study found 9 percent less amyloid in those on bapineuzumab compared with those on a dummy treatment. The drug group had stable levels while the others developed more plaque. Spinal fluid tests on some participants also showed the drug group had less of another substance called p-tau that is released when nerve cells are damaged.

There were potential safety concerns, including six deaths from various forms of cancer among those on bapineuzumab and none in the placebo group. But a wider review of all studies of the drug found that cancer was not more common among users.

"That's not raising any red flags," said an independent expert, Dr. Maria Carrillo, a senior scientist at the Alzheimer's Association. She said the biological changes suggest the drug is helping, so if it's used sooner, "we can perhaps affect cognition."

Salloway's study produced less evidence of benefit. Too few participants had brain imaging to make definitive conclusions about amyloid, and there was just a trend toward less of the nerve-damage substance in the group receiving the higher of two doses tested.

The hopeful signs on biomarkers are "the silver lining" in studies that failed to show the drug was helping patients, said Dr. Eric Yuen, head of clinical development for J&J's Janssen Alzheimer Immunotherapy unit.

Bapineuzumab is given as periodic intravenous infusions, and the companies have said they are stopping development of that form but continuing to test a version that can be given as a shot.

More results on this drug and a similar one — Eli Lilly & Co.'s solanezumab — will be presented at a conference in Boston next month. Lilly recently announced that combined results of two large studies of solanezumab suggested some benefit on cognition.

Brain project predicts connections between neurons

Researchers said a new computerised model of part of a rat's cortex predicts connections between neurons, which could help explain how the brains of mammals - including humans - works.

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Washington - Researchers said on Monday a new computerised model of part of a rat's cortex predicts connections between neurons, which could help explain how the brains of mammals - including humans - works.

“This is a major breakthrough because it would otherwise take decades, if not centuries, to map the location of each synapse in the brain,” said Henry Markram, head of the Blue Brain Project at Switzerland's Ecole Polytechnique Federale de Lausanne.

Launched in 2005, the project aims to develop a virtual mammal brain by 2018.

One of the greatest challenges in neuroscience is to map the synaptic connections between neurons, the statement said, dubbing the so-called “connectome” the “holy grail that will explain how information flows.”

To reconstruct a rat's “virtual cortical microcircuit,” the researchers used data about the geometrical and electrical properties of neurons compiled over 20 years from experiments on slices of living brain tissue.

“Each neuron in the circuit was reconstructed into a 3D model on a powerful Blue Gene supercomputer,” the statement said. “About 10,000 of virtual neurons were packed into a 3D space in random positions according to the density and ratio of morphological types found in corresponding living tissue.”

According to the researchers, whose findings are published in this week's issue of the Proceedings of the National Academy of Sciences, the locations on the model matched that of synapses found in the equivalent real-brain circuit with 75 to 95 percent accuracy.

“Overall, this work represents a major acceleration in the ability to construct detailed models of the nervous system,” according to the statement.