Alzheimer’s Protein Tracked in Injured Brains

(TIME – WASHINGTON) — Scientists for the first time have peered into people’s brains to directly measure the ebb and flow of a substance notorious for its role in Alzheimer’s disease.

The delicate research was performed not with Alzheimer’s patients but with people suffering severe brain injuries — because a brain injury increases the risk of developing dementia later in life.

The goal is to learn why, so that doctors one day might be able to lower that risk.

But with this first-step study, a team of scientists from Missouri and Italy got a surprise.

Too much of that Alzheimer’s-related protein, called beta-amyloid, is thought to be harmful. So the team had expected beta-amyloid levels to spike right after the injury and then drop as patients recovered.

Instead, beta-amyloid levels increased as patients improved and dropped if they got worse, lead researcher Dr. David Brody, a neurologist at Washington University in St. Louis, reported Friday in the journal Science.

What’s going on? Beta-amyloid seems to be a marker of increased brain activity as patients improved.

If so, what started as a study of Alzheimer’s risk might have implications for how the brain-injured are tracked in intensive-care units — although that will take much more research to prove.

“Our study is just the beginning,” Brody said. “Amyloid-beta measurements in the brain may turn out to be a good indicator of how well the cells are communicating with each other.’

Beta-amyloid is best known as the sticky goo that makes up the hallmark plaques inside the brains of Alzheimer’s victims. But it doesn’t start out as gunk. Soluble forms are found in the fluid that bathes the brain, although scientists don’t understand its purpose, or just what happens to trigger formation of those bad plaques.

Nor do they understand how brain trauma so often leads to later Alzheimer’s. One possibility is that extra beta-amyloid speeds whatever dementia-forming process might be lurking among brain cells. Another theory is that the injury decreases a person’s “cognitive reserve,” so that symptoms merely become apparent sooner.

Brody thought brain-injured patients could offer a precious opportunity to start testing that first possibility. These patients were undergoing brain surgery anyway. What if surgeons could insert an extra tiny tube at the same time that would allow hour-to-hour sampling of brain fluid, to measure beta-amyloid?

It’s a technique called intracerebral microdialysis, and colleagues at Washington University already had performed it in mice — linking increased synaptic activity, or communication between brain cells, to increased beta-amyloid.

Brody teamed with Dr. Sandra Magnoni of the Ospedale Maggiore Policlinico, a major trauma center in Milan that has experience with the technique. They asked the families of patients suffering brain injuries from car crashes, falls or hemorrhages from burst blood vessels if they’d agree to the experiment. Eighteen said yes.

Roughly 24 hours after the initial injury, the catheter was placed in patients’ brains, where it stayed for three to seven days. ICU doctors and nurses otherwise provided routine care, tracking patients’ neurologic changes with a standard tool called the Glasgow Coma Score.

Brody tracked the beta-amyloid levels and found they mirrored that coma score, with a direct relationship to each patient’s neurological status.

That means the findings agreed with the previous research on mice. That’s important, as so much Alzheimer’s research must be performed in animals, said Dr. Ramona Hicks, a specialist in traumatic brain injury at the National Institutes of Health, which helped fund the work.

Brody cautions that beta-amyloid might have spiked in everyone right at the time of injury, something his study started too late to measure.

Also, it only measured total beta-amyloid levels, not a strung-together form that’s thought to be toxic to cells, something Brody hopes to try next.

While the work raises more questions than it answers, it brings researchers a valuable new tool for studying both Alzheimer’s risk and just what happens during brain-injury recovery.

“It sort of sets a platform for future studies,” said NIH’s Hicks.

Alzheimer’s Research Holds Promise

When it comes to Alzheimer’s disease, there hasn’t been much to celebrate in recent years. Efforts to develop a vaccine against the brain disorder have stalled, and no drugs have been able to reverse the slow death of neurons that robs people of their memories and thoughts. For the first time in many years, however, researchers in the field are genuinely excited about the potential for effective drug treatments and helpful new risk factors.

Scientists gathered this week at the Alzheimer’s Association’s International Conference on Alzheimer’s Disease in Chicago, presenting a slew of promising results from drug trials, a new understanding of how the neurological disease works and insights into the way social and lifestyle factors may affect its progression. “On the one hand, Alzheimer’s disease is a complex pathologic process, and that is daunting,” says Dr. Ronald Petersen, chair of the Alzheimer’s Association’s medical and scientific advisory council and director of the Mayo Clinic Alzheimer’s Disease Research Center. “But now we are beginning to segregate out different therapeutic targets and develop drugs that have an impact on each target, so in combination they may handle the disease better than any single approach.”

The potential success of the combination strategy was borne out in some of the conference’s most exciting papers. Researchers from Mount Sinai School of Medicine reported, for example, that compared with other Alzheimer’s patients, those who had diabetes and took insulin plus another anti-diabetes medication to control blood sugar had 80% fewer amyloid plaques — the sticky brain-clogging masses that, together with protein tangles, are the hallmarks of Alzheimer’s disease. Although the mechanism wasn’t entirely clear, researchers think the drugs may work by normalizing the brain’s communication network of insulin receptors, which goes awry in the Alzheimer’s brain, while clearing away the damaging plaques.

In a separate trial, an experimental drug called rember, developed by a Singapore-based company, also showed some promise in a safety study. Among 321 patients, rember appeared to stall advancement of the disease, degrading the protein tangles that build up in Alzheimer’s brains. Potentially, a combination of drug therapies — designed to prevent both plaques and tangles — may prove effective in slowing the progression of the disease.

But future approaches won’t stop with drug treatments. Petersen notes that researchers are also forging ahead with innovative screening tests to identify Alzheimer’s patients sooner — before too much deterioration occurs in the brain. Better screens could also potentially identify patients by the specific type of brain buildup — plaques vs. tangles — that is causing them the most severe problems. That kind of triage early on could help doctors target the right patients with the most effective therapies.

Alzheimer’s doctors also reported new discoveries about certain lifestyle factors that may accelerate or slow the dementia that often precedes Alzheimer’s. Swedish psychologists studied rates of the disease in a sample of 1,449 people over a period of 21 years. They found, as previous research has suggested, that single people have up to twice the risk of developing Alzheimer’s as their married counterparts. But what was unexpected was the finding that the reason for a person’s singlehood impacts his or her risk. Compared with other singletons, people who were single as a result of divorce or widowing had a three times and six times greater risk, respectively. “This was quite unexpected,” says Krister Hakansson, who led the study and is a lecturer in psychology and a Ph.D. candidate at Vaxjo University and the Karolinska Institute. “We established the association, but when it comes to explaining it, we can only speculate at this state.”

One reason for the higher risk could be that those who had the cognitive protection and social benefits of a relationship but lost them may be worse off than those who never enjoyed those benefits at all; or perhaps the emotional toll of losing a close partner damages cognitive functions in a way that puts these people at greater risk for dementia and Alzheimer’s down the line. Either way, says Hakansson, the results suggest that “if you are looking for interventions to prevent Alzheimer’s, one way may be to identify people who have been divorced or widowed, and who haven’t adapted or gotten back into the social circle, and give them support with the aim of giving them new structure and social networks in their lives.”

As more discoveries are made, researchers hope they’ll develop a better understanding of who is most at risk of Alzheimer’s disease, how each patient’s case is unique, and how best to treat specific patients with the drug and lifestyle changes that will be most effective for them. Taken together, these approaches could one day make the long goodbye of Alzheimer’s a thing of the past.

Alzheimer’s drug ‘halts’ decline

UK scientists have developed a drug which may halt the progression of Alzheimer’s disease.

Trials of the drug, known as rember, in 321 patients showed an 81% difference in rate of mental decline compared with those not taking the treatment.

The Aberdeen University researchers said the drug targeted the build-up of a specific protein in the brain.

Alzheimer’s experts were optimistic about the results, but said larger trials were now needed.

Presenting the results at the International Conference on Alzheimer’s Disease, Professor Claude Wischik said the drug may be on the market by 2012.

This bodes well for a Phase III trial, but we need more human trials to assess the treatment’s possible side effects Rebecca Wood, Alzheimer’s Research Trust

Patients with mild to moderate Alzheimer’s disease were given either 30, 60 or 100mg of the drug or a placebo.

The 60mg dose produced the most pronounced effect – over 50 weeks there was a seven-point difference on a scale used to measure severity of dementia.

At 19 months there was no significant decline in mental function in patients taking the drug, the researchers said.

Imaging data also suggests the drug may be having its biggest effect in the parts of the brain responsible for memory.

The link between clumps or “tangles” of protein inside nerve cells in the brain and Alzheimer’s disease was first made over 100 years ago.

Later shown to be made up of a protein called Tau, the tangles build up inside cells involved in memory, destroying them in the process.

SUCCESS STORY Among the trial patients was Jimmy Hardie, 72. He began taking Rember in March 2006. His wife said his improvement was gradual, but he is now much more confident. She said he used to panic when faced with something difficult to do, but now copes much better. He keeps busy maintaining old tractors, running a trout fishery, and doing a lot of gardening. Mr Hardie said: “It has made a difference to my life. I have my off days – but I had a lot before.”

Rember, or methylthioninium chloride, is the first treatment specifically designed to target the Tau tangles.

Other treatments for Alzheimer’s tend to focus on combating a waste protein in the brain, beta-amyloid, which is known to form hard plaques. The latest work suggests targeting Tau may produce better results.

Methylthioninium chloride is more commonly used as a blue dye in laboratory experiments.

Professor Wischik discovered it by accident 20 years ago, when a drop in a test tube led to the disappearance of the Tau protein he had been working on.

“We have demonstrated for the first time that it may be possible to arrest the progression of this disease by targeting the tangles which are highly correlated with the disease,” he said.

“We did an analysis of the effect size at 24 weeks and at 50 weeks compared to the average effect size of the current treatments and it was about two and a half times better,” he added.

Larger trials of the drug are planned to start in 2009, and researchers are also investigating whether the drug has a role in prevention of the disease in the first place.

Professor Clive Ballard, head of research at the Alzheimer’s Society, said: “This is a major new development in the fight against dementia.

“It is the first realistic evidence that a new drug can improve cognition in people with Alzheimer’s by targeting the protein tangles that cause brain cell death.

“This first modestly sized trial in humans is potentially exciting.

“It suggests the drug could be over twice as effective as any treatment that is currently available.”

Rebecca Wood, chief executive of the Alzheimer’s Research Trust, said: “In this exploratory trial, rember reduced the decline in blood flow to parts of the brain that are important for memory.

“This bodes well but we need more human trials to assess the treatment’s possible side effects.”

She added the fact the trial was funded by a pharmaceutical company highlighted the lack of funding for Alzheimer’s research in the UK.