Newest approach to “Plaque Busters”

By Joel Ross | September 9, 2010

There has been a huge amount of coverage on Alzheimer’s Disease with the NY Times writer, Gina Kolata covering a huge amount of topics which will be address on subsequent posts so stay tuned readers.

Lilly recently had a terrible set back as did the many patients enrolled in their study testing what is known as a “gamma secretase inhibitor”. The treated AD patients fared worse than those given a placebo and those taking their compound had higher rates of skin cancer. A big blow for Lilly indeed and makes all other pharmaceutical companies look even harder for that “magic bullet” to remove toxic plaque or slow or even prevent its production.

New Alzheimer’s approach may sidestep early snags
3:35pm EDT
* Compounds alter but do not block gamma secretase
* Neurogenic Pharmaceuticals hopes to do human trials
By Julie Steenhuysen
CHICAGO, Sept 8 (Reuters) – A new Alzheimer’s compound kept toxic clumps from forming in the brains of mice, without causing side effects seen in similar drugs, U.S. researchers said on Wednesday.
They said the drug changes the way an enzyme called gamma secretase works, without completely blocking it, an approach that so far has failed in human trials.
Instead, the new compound just tinkers with the machinery a bit, said Steven Wagner, a neuroscientist at the University of California, San Diego School of Medicine who led the research published in the journal Neuron.
“We can tweak it,” Wagner said in a telephone interview.
Several companies, including Eli Lilly (LLY.N: Quote, Profile, Research, Stock Buzz), have been developing gamma secretase blockers in hopes of warding off brain-damaging clumps of a protein called beta amyloid, which kill brain cells and wipe out thinking and memory in people with Alzheimer’s disease.
But gamma secretase also plays an important role in everyday cell function.
The trick was to find a way to keep the bad proteins from forming without interfering with other essential brain functions, Wagner said.
The team screened thousands of molecules looking for one that would modify the enzyme in just the right way.
They tested several of these in genetically engineered mice that develop Alzheimer’s-related brain plaques.
One chemical, compound 4, kept brain plaques from forming, but left other brain processes alone.
The results were so promising at reducing levels of the protein that a private San Diego-based company called Neurogenetic Pharmaceuticals Inc has licensed the patent. The company has dubbed it NGP 555.
“It is something they are ultimately going to try to test in humans,” Wagner said.
The hope is to avoid problems seen with similar drugs, such as Lilly’s failed drug semagacestat, which tried to broadly knock down the activity of the enzyme.
Patients enrolled in Eli Lilly’s late-stage study of semagacestat actually had their brain function get worse, and some developed a form of skin cancer.
“Our approach is to target and inhibit only the production of key peptides that may play a pivotal role in the pathogenesis of Alzheimer’s disease,” Wagner said in a statement.
More than 5 million Americans have Alzheimer’s disease — more than 26 million people worldwide.
Current drugs only treat symptoms, but no drug arrests the steady mental decline that robs victims of the ability to think and care for themselves. (Editing by Jerry Norton)

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Possible Huge Breakthrough in non-invasive detection of Amyloid

By Joel Ross | July 27, 2010

For many years scientists have been focusing on finding non invasive ways to locate the “holy grail” of Alzheimer’s Disease (or what I have referred to as “amyloid associated memory impairment, AAMI). Perhaps finally we have arrived. Please read below:

Honolulu: FDA Approval in Sight for 18F Amyloid Tracer Florbetapir?

13 July 2010. Regulatory approval could be on the horizon for an amyloid tracer that is widely considered the frontrunner among several 18F-labeled compounds being developed for brain imaging using positron emission tomography (PET). Even the skies of Honolulu, which hosts the Alzheimer’s Association’s International Conference on Alzheimer’s Disease (ICAD) from 10-15 July 2010, could not have been sunnier than the Phase 3 histopathology data reported Sunday by Christopher Clark of Avid Radiopharmaceuticals, Philadelphia, Pennsylvania. He and colleagues found near-perfect correlation between PET imaging using the new tracer and amyloid load measured postmortem in the same patients. Given these encouraging results, the company plans to submit an application by late summer to the U.S. Food and Drug Administration (FDA), which could, so the company hopes, approve the compound as soon as six months thereafter under expedited review, Clark told ARF. A validated F18 PET tracer would expand the commercial availability of amyloid imaging, which has thus far been restricted largely to some 60 or so research centers worldwide.

In this study, Avid tested florbetapir (formerly 18F AV-45) in 35 people who were expected to die within six months. The idea was that imaging people near the end of their lives would minimize the time interval between PET scan and histopathological evaluation, allowing researchers to more effectively compare the two measures of brain amyloid load. To test their PET reagent’s specificity, the team also imaged 47 people who were highly unlikely to have detectable brain amyloid—namely, young, cognitively normal subjects without an ApoE4 allele. On average, less than three months elapsed between PET imaging and death, about 11 hours between death and autopsy, Clark said.

Of the 19 subjects who met NIA-Regan criteria for AD pathology, all but one were amyloid-positive on PET as judged by visual reads (97 percent accuracy), and all 19 came out positive on SUVR quantification of PET data (100 percent accuracy). For both PET analysis methods, all 16 who lacked postmortem AD pathology were also amyloid-negative by live brain imaging, giving the tracer 100 percent specificity in this study.

The data drew praise from the neuroimaging community, which might have expected as much given that florbetapir already looked promising in Avid’s analysis of six autopsy cases presented earlier this spring at the Human Amyloid Imaging meeting and in more detail at the American Academy of Neurology conference, both in Toronto (see ARF related news story).

“These data are excellent,” said Chris Rowe of the University of Melbourne. Other scientists’ informal hallway comments ranged from enthusiasm that the availability of an approved agent to image a key AD pathology would transform the clinical trial landscape, to more guarded optimism. Some scientists cautioned that it remained to be seen whether insurance will pay for amyloid imaging, and noted that this measure may add more value to clinical detection of early cases for research purposes than for routine diagnosis in the community.

Florbetapir appears useful for predicting whether seniors with mild cognitive impairment were likely to decline further, as reported in a separate talk at ICAD by Reisa Sperling of Brigham and Women’s Hospital in Boston. She and colleagues reported follow-up data on a florbetapir Phase 2 study. The scientists have data thus far on 138 of 184 cognitively normal, newly diagnosed MCI and AD participants in the study. After getting their brains imaged with florbetapir at baseline, the participants had their symptoms assessed every six months through phone interviews, and returned for clinical and neuropsychological evaluation at 18 months. None of the healthy seniors worsened noticeably within that timeframe, regardless of brain amyloid status. However, in the MCI group, a greater proportion of amyloid-positive subjects progressed to AD than did amyloid-negative MCI patients, suggesting that amyloid imaging using florbetapir may help identify those at risk for progressive cognitive decline. In his talk, Rowe broadly reviewed ongoing longitudinal assessments of various MCI cohorts imaged with several of the amyloid imaging agents currently in development at his center and elsewhere. The overall trend there, too, was that MCI patients who have amyloid in their brain go on to meet an AD diagnosis over the next two to four years, while amyloid-free MCI patients generally do not.—Esther Landhuis.

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AVID may hit a Home Run in Preventing Alzheimer’s Disease

By Joel Ross | June 25, 2010

Promise Seen for Detection of Alzheimer’s
I have been blogging quite often on the topic of “amyloid” buildup in the brains of patients with Alzheimer’s Disease and for those who have no memory loss (yet) but with amyloid detected in the brain. What good is it to know you might ask, that this sticky/gooey material is starting to destroy brain cells by the millions perhaps every day if nothing can be done to stop it. The answer is simple: Studies being conducted at my three Memory Enhancement Centers (Brooklyn NY, Eatontown and Toms River NJ) are testing new medications to see if they can delay onset of Alzheimer’s Disease using chemical designed to slow production of the body’s amyloid. The theory is simple: reduce production of the toxic amyloid and the brain might start healing itself.
The study is sponsored by Bristol Myers Squibb and is seeking volunteers who satisfy very strict criteria to participate. Click on the link I have on the bottom right under Bristol Myers Squibb to learn more about the amyloid lowering study.
In terms of the article covering Dr. Skovronsky’s in the NY Times, he has possibly discoverd/created an entire new approach to early recognition of high risk patients who might soon develop memory loss and then more serious dementia symptoms of the Alzheimer’s type.
Just like treating cholesterol in “high risk” younger adults for many years to reduce the risk of stroke, heart attack and peripheral vascular disease, now it is in my opinion highly likely we can do the same with amyloid plaque.
My readers recall that I do not favor the term Alzheimer’s Disease as I have never met a patient with this condition in my 29 years of being an MD, that was pleased to hear or even share the diagnosis with other. However, my term “Amyloid Associated Memory Impairement” or AAMI is simple to understand and say “Ahmee” or “AMEE”. It requires the presence of amyloid (using the AVID scan for example) plus any degree of memory loss considered worse than should be expected for ones age. This will require the doctor such as a geriatrician (like myself), neurologist, geropsychiatrist, psychiatrist and/or neuropsychologist.
Stay tuned for more exciting news from the Memory Enhancement Centers of America!

By GINA KOLATA
Published: June 23, 2010

The Vanishing Mind
A Diagnostic Tool

Articles in this series are examining the worldwide struggle to find answers about Alzheimer’s disease.

Times Topics: Alzheimer’s Disease

Dr. Daniel Skovronsky at Avid Radiopharmaceuticals in Philadelphia, telling his staff about the results of a study that showed that the company’s test for Alzheimer’s appeared to be effective.
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A few minutes later, the message arrived — results that showed his tiny start-up company might have overcome one of the biggest obstacles in diagnosing Alzheimer’s disease. It had found a dye and a brain scan that, he said, can show the hallmark plaque building up in the brains of people with the disease.

The findings, which will be presented at an international meeting of the Alzheimer’s Association in Honolulu on July 11, must still be confirmed and approved by the Food and Drug Administration. But if they hold up, it will mean that for the first time doctors would have a reliable way to diagnose the presence of Alzheimer’s in patients with memory problems.

And researchers would have a way to figure out whether drugs are slowing or halting the disease, a step that “will change everyone’s thinking about Alzheimer’s in a dramatic way,” said Dr. Michael Weiner of the University of California, San Francisco, who is not part of the company’s study and directs a federal project to study ways of diagnosing Alzheimer’s.

Still, the long tale behind this finding shows just how difficult this disease is and why progress toward preventing or curing it has been so slow.

Ever since Alzheimer’s disease was described by a German doctor, Alois Alzheimer, in 1906, there was only one way to know for sure that a person had it. A pathologist, examining the brain after death, would see microscopic black freckles, plaque, sticking to brain slices like barnacles. Without plaque, a person with memory loss did not have the disease.

There is no treatment yet to stop or slow the progress of Alzheimer’s. But every major drug company has new experimental drugs it hopes will work, particularly if they are started early. The questions though, are who should be getting the drugs and who really has Alzheimer’s or is developing it?

Even at the best medical centers, doctors often are wrong. Twenty percent of people with dementia — a loss of memory and intellectual functions — who received a diagnosis of Alzheimer’s, did not have it. There was no plaque when their brains were biopsied. Half with milder memory loss, thought to be on their way to Alzheimer’s, do not get the disease. And with such a high rate of misdiagnosis, some who are mistakenly told that they have Alzheimer’s are not treated for conditions, like depression or low levels of thyroid hormone or drug side effects and interactions, that are causing their memory problems.

Brain scans that showed plaque could help with some fundamental questions — who has or is getting Alzheimer’s, whether the disease ever stops or slows down on its own and even whether plaque is the main culprit causing brain cell death.

Dr. Skovronsky thought he had a way to make scans work. He and his team had developed a dye that could get into the brain and stick to plaque. They labeled the dye with a commonly used radioactive tracer and used a PET scanner to directly see plaque in a living person’s brain. But the technology and the dye itself were so new they had to be rigorously tested.

And that is what brought Dr. Skovronsky, a thin and eager-looking 37-year-old, to his e-mail that recent day.

Five years ago, Dr. Skovronsky, who named his company Avid in part because that is what he is, had taken a big personal and professional gamble. He left academia and formed Avid Radiopharmaceuticals, based in Philadelphia, to develop his radioactive dye and designed a study with hospice patients to prove it worked.

Hospice patients were going to die soon and so, he reasoned, why not ask them to have scans and then brain autopsies afterward to see if the scans showed just what a pathologist would see. Some patients would be demented, others not.

Some predicted his study would be impossible, if not unethical. But the F.D.A. said it wanted proof that the plaque on PET scans was the same as plaque in a brain autopsy.

The Avid study was designed to provide that proof. And the full results, contained in the e-mail message sent that day, May 14, were the moment of truth. When he saw them, Dr. Skovronsky said they were everything he had hoped for.

“This is about as good as it gets,” he said that day.

He went into a rotunda that serves as Avid’s lunchroom to tell the company’s 50 employees. “This is a big day for us,” he continued. “I thought about what I would say, but I have totally forgotten it.”

His employees applauded. Then they had champagne in blue plastic cups.

A First Dye

The type of scans used in this study, PET scans, are expensive and patients have to go to a scanning center, get injected with a radioactive dye, wait for the dye to reach their brain and then have a scan.

Other tests are being studied — ones that look for amyloid in cerebrospinal fluid that bathes the brain; MRI scans that look for shrinkage of the brain in areas needed for memory and reasoning; PET scans that look for uptake of glucose, a cellular fuel, to show areas where the brain was active and where it was not. The tests, though, were not necessarily specific for Alzheimer’s and none had been studied to see if they accurately predicted plaque on autopsy.

Earlier this decade, two scientists at the University of Pittsburgh developed an amyloid dye that while not practical for widespread use, stunned scientists by showing it seemed possible to see amyloid in a living brain.

The researchers, Chester Mathis and William Klunk, began their work two decades ago, persevering even though they had no research money. In the first 10 years, they tested more than 400 compounds. When they finally found one that seemed promising, they tested more than 300 variations.

“On and on it went,” Dr. Mathis said.

Finally, in late 2001, they began working with collaborators in Sweden to test their dye in humans.

On Valentine’s Day 2002, the Swedish researchers injected the first Alzheimer’s patient with the dye, known as Pittsburgh Compound B, and scanned the patient’s brain.

It worked, the Swedish doctors told Dr. Mathis in an excited phone call.

A PET scan showed amyloid exactly where it would be expected. The Swedish doctors were convinced they were seeing actual plaque. They told Dr. Mathis it was time to celebrate.

But Dr. Mathis worried. What if the same pattern occurred in people without Alzheimer’s?

Two weeks later, he got another call from Sweden. His colleagues had scanned a person without Alzheimer’s. There was no sign of telltale plaques.

His sweet reward came in July 2002, when the scans were shown to an audience of 5,000 scientists at an international conference on Alzheimer’s.

“There was an audible gasp,” Dr. Mathis said. “The field was taken aback.”

“The rest is history,” he added.

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Mild Cognitive Impairment

By Joel Ross | June 24, 2010

Below is an excerpt from arguably one of the leading experts in the field of MCI. The sooner we seek treatment for memory loss, the better the outcome.

Mild cognitive impairment: A way station along road to Alzheimer’s
By Angela Lunde

(Ronald Petersen, M.D., Ph.D., is the director of the Mayo Clinic Alzheimer’s Disease Research Center. Below is an excerpt from an article he wrote that I thought you may find interesting.)
An unprecedented global shift toward an aging population has brought with it an increase in the occurrence of cognitive impairment such as Alzheimer’s disease. With the baby boom generation beginning to arrive at the age of risk, this issue may be approaching crisis proportions that may bankrupt the health care system as we know it.
In the field of age-related dementia, there’s likely a continuum from normal aging through a stage often called mild cognitive impairment on to dementia. The challenge for clinicians lies in assessing the question: “How much forgetfulness is too much?” Some incidental episodes of forgetfulness — “Where are my car keys?” — are likely common expressions of normal aging. However, when individuals begin to forget important information such as doctors’ appointments and, most importantly, when they do this on a repeated basis, and when a person’s friends and family begin to notice forgetfulness in the individual, it’s time to seek medical attention.
A great deal of research in aging and dementia is now focused on mild cognitive impairment — a clinical condition in which people are more forgetful than they used to be, and more than they ought to be. And although their function around the community may be relatively normal, when these individuals seek a medical evaluation the degree of forgetfulness exceeds what would be expected for that person’s age and education.
At Mayo Clinic in Minnesota, investigators are pursuing these issues in the Mayo Clinic Study of Aging. This project is a study over time of 2,000-3000 persons randomly sampled between the ages of 70- to 89-years old. At each annual visit, information is acquired, including mild cognitive impairment scans, blood samples for DNA and plasma proteins, historical data on cognitive and intellectual activities, dietary information, a quantitative assessment of gait, and a measure of olfactory functioning, which can be associated with degree of dementia in Alzheimer’s.
The long-term goal of this project is to describe trajectories of successful aging, typical aging, and impaired aging from a cognitive perspective. Ultimately, we hope to identify a model that might be useful at predicting who is going to follow which of the three aging trajectories. When disease-modifying therapies become available, this model could help clinicians decide when and how to intervene with individual patients. It may well be that studies performed in Minnesota will inform the worldwide community about this pending crisis.

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Does Gingko do any good at all?

By Joel Ross | June 23, 2010

Many of my patients take Gingko despite no FDA approval for this supplement.
Many studies have shown convincingly it is worthless to take as well as expensive. Now another study is published which claims to have a huge protective effect compared to placebo in a four year followup of 2584 patients with “memory loss”. The results showed very few in both groups in 4 years of followup developed a diagnosis of Alzheimer’s Disease.
Although there was statistical significance favoring use of Gingko compared to placebo these subjects did not undergo rigorous testing with brain scans prior to taking Gingko or placebo to determine what risk they were to develop AD in the first place. This flawed study again points out the need for very careful analysis by experts and the regulatory authorities to review the protocol before it starts. Because it is a “supplement” perhaps the French did not put enough thought into more carefully giving input to the sponsors.

The study should have had PET scans for amyloid in all subjects (too expensive for the manufacturer to pay for). Those who had high amyloid loads in the brain would be very good candidates to participate and if indeed those with high amyloid levels had less development of AD by taking gingko vs. placebo, the results would be tremendously well accepted by me and others in the neuroscience community.

So readers look very carefully at their claims and I would rather simply enjoy looking at the beauty of gingko trees. Avoid the female trees at times since according to Nature Hills Nursery, a gardening and landscaping store that sells ginkgo trees, the female trees drop small, plum-shaped fruit with “foul-smelling and mildly toxic skin.”

“Butyric acid makes them smell,” Selter said. “It also keeps them from rotting and keeps them from being eaten.”

Butyric acid is also found in rancid butter, Parmesan cheese and vomit.they have a very strong odor) and don’t waste time ingesting their extracts.

New Results in Dementia Research: Major Study Shows That Long-Term Intake of Ginkgo Biloba Special Extract EGb 761® Protects against Alzheimer’s Disease

Press Release Source: Dr. Willmar Schwabe GmbH & Co. KG On Tuesday June 22, 2010, 9:24 am EDT
KARLSRUHE, Germany–(BUSINESS WIRE)–For the very first time, a medicine has been shown to protect against the development of Alzheimer’s disease. French scientists were able to demonstrate that taking 240 mg of Ginkgo extract EGb 761® per day regularly over a period of at least 4 years can cut the risk of developing Alzheimer’s disease by nearly 50%.
“The results of the GuidAge study are remarkable”, according to Prof. Michael Habs, Managing Director at Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, producers of EGb 761® (Tebonin®, pharmacy only). “It is the first time ever that a protective effect against Alzheimer’s disease has been demonstrated for a medicine. The multifaceted effects of the plant extract appear to positively influence the complex developmental processes of dementia.”
The GuidAge study was a large-scale study, in which 2854 elderly people with memory complaints were randomly assigned to receive either 240 mg/day of the patented Ginkgo special extract or a placebo for five years. Of those subjects taking the study medication for at least 4 years 29 out of 966 (3.0 %) taking placebo developed Alzheimer’s disease; in contrast only 15 out of 947 (1.6 %) treated with EGb 761® developed the disease (p=0.03) (Press release IPSEN, June 22, 2010). The result of this prospectively planned analysis shows that the Ginkgo special extract developed by Dr. Willmar Schwabe Pharmaceuticals can lower the risk of dementia by 47%.
The brain pathology that leads to overt Alzheimer’s disease develops over the course of many years. It is therefore not surprising that those study participants who developed dementia early in the study gained less protective benefit from EGb 761® treatment, because they already had the disease. When these subjects as well as those who left the study prematurely, i.e. all study participants were included in the analysis, the overall treatment effect was still detectable, although not statistically significant.
The results were commented on as follows by Prof. Ralf Ihl, University of Duesseldorf and director of the Department of Geriatric Psychiatry, Maria-Hilf Hospital, Krefeld: „There have been hints that Ginkgo biloba may exert a preventive effect. With the findings of this study we have first scientifically verifiable results suggesting that the extract may be useful for preventing the development of Alzheimer’s disease.“
The result of the GuidAge study agrees with the findings of two earlier cohort studies carried out in France, which also suggested a protective effect of EGb 761®. A study funded by the US National Institute on Aging as well found a dementia-protective effect in those subjects, who had taken their medication regularly. In another US study, a protective effect was not found, however. But towards the end of this study, the medicine was actually only taken by little more than half of the subjects. The results of the GuidAge study now again confirm the importance of a regular and long enough intake of 240 mg EGb 761® per day: A very high proportion of 93% of the participants took their medication regularly during the whole treatment period. Once again the excellent long-term safety profile of EGb 761® was confirmed.
Animal models also showed that EGb 761® intervenes in several of the processes decisive to the development of Alzheimer’s disease: the formation of harmful protein-compounds (so-called β-amyloid) is inhibited and the nerve cell damage caused by these as well as by ageing processes reduced so that energy generation in the nerve cells can be maintained. The patented special extract EGb 761® contains a particularly high proportion of plant substances that are unique to Ginkgo, ginkgolides and bilobalide, and that are especially important for the protection of nerve cells.
The efficacy of EGb 761® in the treatment of dementia diseases has been confirmed recently in several meta-analyses of available studies. EGb 761® can also improve cognitive performance in people who do not yet show significant impairment. In summarizing the study results, Dr. Reiner Kaschel, reader in clinical neuropsychology at the University of Osnabruck, concluded: “Meta-analyses of the data by independent scientists consistently substantiate the efficacy of EGb 761® at the onset of cognitive decline.”

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Newest approach to “Plaque Busters”

Possible Huge Breakthrough in non-invasive detection of Amyloid

AVID may hit a Home Run in Preventing Alzheimer’s Disease

Mild Cognitive Impairment

Does Gingko do any good at all?