When the Box is Empty

The King had a modest kingdom. He was Danish. This meant he was proud, tall, athletic and he enjoyed a quick wit. He was married to a princess from Great Britain at a very young age. They were both really just children when they began their own family.

They had three children, two boys and a girl. The children all shared one common aim, to make the King proud. Each child vied for the King’s attention and love, each using a different strategy.

The eldest son used music to make his father proud. The middle child, the daughter used humor and dancing. The youngest chose sports, knowing his father had once been a great athlete, a champion in several sports.

They had a modest castle, the King always worked hard to provide for his family. Demonstrating affection wasn’t something he was ever comfortable with. So, in his own way, he captured treasured moments by making or collecting trinkets. Each little symbol represented a special family moment. Some were shiny, golden; still others were like little bells that made a sound when you picked them up. There was a story for each trinket.

You see the King was a gifted storyteller. At dinner he would open up the box and hold up a trinket and smile. He would look up and to the right, and then tell a wonderful story that would have the children laughing, crying or shaking their head in disbelief.

Telling stories became a family tradition.

He encouraged the children to begin collecting their own trinkets and stories.

As it is with most children, they obeyed their father and began filling up their boxes with symbols. Though the children were
never very close, there were moments of family joy. They were all very busy trying to please the King with their respective gifts.

As the years went by, the Kings Box became a giant chest, ornate, hand carved and full of trinkets. As the King grew older the quality and quantity of the contents of the chest improved. Soon the children had children of their own and they maintained the ritual of stories at the dinner table.

One day, the King reached in his box for a specific trinket and found it missing.

Thinking this somewhat odd, he thought perhaps he might have given it to his youngest son. He forgot about it. The next day, the same thing happened; a specific trinket was not to be found.

What the King did not know was a thief had snuck in the night and stolen the shiniest trinket. The thief liked the trinket so much, the next night he took a different one.

Because there were so many at first the King didn’t notice. You see, this thief in the night was relentless, insidious, crafty and brutal. He was sneaking into his chambers and quietly pinching the King’s most treasured possessions, his memories.

One night the Queen heard a noise that startled her. She lit a match and held up the candle beside the bed. Holding it up high
she saw the thief…it was a raccoon! He had a little bell in his hands. The light scared him and he scurried off with the bell.

The queen had long since suspected something was wrong, now she knew. She gave it a name. That terrible raccoon. The King
wasn’t crazy and neither was she. Something really was taking the King’s most treasured gifts.

The next day they put a lock on the chest. That would stop the thief. The raccoon was too crafty. He picked the lock and kept
stealing trinkets every night. The queen tried an alarm, a special light, and guard dogs, nothing worked. Each night the raccoon kept stealing the King’s prizes. One day the box was empty! It was a sad day in the kingdom. The children came and sat at the feet the of the King and Queen and cried.

There was nothing to do.

All the memories were gone. The King had no more stories to tell. He was silent. He sat there with a far away look. That was how it was going to be. That is life when the box is empty.

After a time, when the pain of the empty box came a little easier to accept, the Queen said to her children, go home, go through your chests, your boxes of trinkets. Choose the best ones. Each time you come to visit the King, bring a trinket and we shall put it in your father’s box. We shall tell that story, and laugh, cry and enjoy it as something special. I will guard it.

I will keep a constant vigil. In this way, the raccoon can never take your stories. When we get together we shall honor the King in this special way.

So it was, once a week, the children would bring their children for a visit and drop a trinket in the box. This brought the children together in a way that never existed before.

The raccoon was very unhappy about all this. He still tried to get in the castle, but the love of the family kept him on the outside, looking in. Though he tried to keep stealing as thieves do, he never took another trinket.

Love does that. It’s not something even the smartest thief in the world can take. That was the lesson learned in the Kingdom.

The box was full until the day the King finally passed away. When he did, he was surrounded by children, grandchildren, stories, trinkets and love.

Only one life that soon is past; only what’s done with love will last.

To people all over the world, that ever suffered the terrible pain of losing a loved one to Alzheimer’s. I understand your pain. The night I read this story to my youngest son Evan, we wept together, holding each other tight. I pray science one day finds a cure for this terrible disease. In the meantime, may this little story bring you and your family comfort. May it bring your family a little closer together, as it has mine. Send this story to someone you know that is suffering. Perhaps it will heal the pain of loss for them or their children just a little bit. Grief is a form of energy and must find a way out. My hope is you make the time to put some trinkets in your family’s box. It won’t feel quite so empty.

New Hope for Alzheimer's Treatment

There is now widespread agreement among research scientists and medical professionals that Alzheimer’s Disease (AD) is a problem quickly growing to vast proportions. As the life expectancy of Americans continues to rise, increasing the percentage of the population over 65 years of age, so does the number of Alzheimer’s cases.

It is currently estimated that people over 65 years of age have a 10% chance of developing Alzheimer’s, while those over 85 have a 50% likelihood of developing AD, making it the leading cause of dementia among older people. Though the disease is associated primarily with memory loss, its effects also comprise a number of other severe disabilities, including changes in personality, disorientation, difficulty with speech and comprehension, and a lack of ability to move normally.

Consequently, most Alzheimer’s patients require a great deal of care, costing society close to $100 billion annually. According to Christian Fritze, Ph.D., Director of the Antibody Products Division at Covance Research Products, "The impact of Alzheimer's Disease on our society will only increase as our population ages. The prevalence of the disease and disabling effects on the patient are significant by themselves. In addition we are becoming increasingly aware of the far-reaching effects on families, care-giver networks and the economics of our health care system. The drive for progress towards effective treatments by the research and drug development community is growing stronger every day."

A New Consensus

But recent developments in the medical research community do provide some hope. During the last two years, there has been a growing consensus among Alzheimer researchers about the cause of Alzheimer’s disease, providing focus for scientists exploring the new treatment options.

The focus is on amyloid beta oligomers, a new wrinkle on an older hypothesis called the “amyloid cascade hypothesis”. Widespread acceptance of this new conclusion is something of a milestone in the history of Alzheimer’s research. As Dr. Fritze says, "The decades old quest for the causative agent in Alzheimer's Disease has recently focused on the precursors of amyloid plaques. These precursors are part of a bewildering array of processed (APP) Amyloid Precursor Protein) variants, Tau isoforms and secretase components that play a role in neuronal cytotoxicity and subsequent brain dysfunction.”

Amyloid plaques are sticky protein deposits in the brain containing amyloid beta peptide. Researchers have associated the buildup of this plaque with Alzheimer’s disease since its discovery in 1907. But despite the clear correlation, scientists were not sure what, exactly, spurred the onset of Alzheimer’s Disease.

The hypothesis that amyloid beta accumulation in the brain is the major cause of Alzheimer’s Disease1 has been the focus of much attention over the past decade. Although this hypothesis was the leading explanation for the cause of AD, it had several weaknesses. The most obvious problem with the theory was the fact that the buildup of amyloid beta peptides did not necessarily correspond with the severity of Alzheimer’s symptoms.

However, in 19982 and in 20023, researchers proposed that it was not the amyloid beta plaques themselves that were neurotoxic – and therefore the cause of Alzheimer’s – but rather precursors to amyloid beta plaques formed by smaller aggregates of amyloid beta. These new ideas are gaining widespread acceptance among the Alzheimer’s research community, creating a consensus that had not existed before.

This new focus provides one more spur to action for Alzheimer’s researchers, and underscores the need for further advancement. “The AD field demands sophisticated, highly-sensitive research tools to track these components and quantitate the existence of monomeric, oligomeric and fibrillar amyloid forms present in the progression of Alzheimer's disease,” says Dr. Fritze.

Antibody Treatment

Two new studies, both released in October 20044, suggest that new treatment options may be on the horizon. The studies are the modification of one of two previous attempts using amyloid beta (Aβ) antibodies in the treatment of Alzheimer’s Disease. The previous attempts, though not successful, did at least suggest new courses of action in Alzheimer’s research and provided invaluable information for researchers.

In the first of the two previous attempts, researchers injected the antigen itself – pieces of the beta amyloid protein that makes up amyloid plaque – into mice, in the hopes that the injections would generate an immune (antibody) response against amyloid. Results were initially positive. The injected antigen produced Aβ antibodies and slowed the onset of the disease by decreasing Aβ levels. However, when tried on humans, the procedure led to meningoencephalitis (an inflammation of tissue around the brain) in some patients, and was therefore halted.

In the second attempt, a passive immunity therapy was tried in which antibodies to amyloid beta (not amyloid protein) were injected into mice, but hemorrhaging and inflammation ensued due to the high antibody doses required to be effective.

New Hope

But now there appears to be new hope for the use of antibodies as therapeutic agents for the treatment of Alzheimer’s patients. In the first of the two new studies that appeared in October conducted by the National Institute for Longevity Sciences, NCGG, and the Center for Neurological Diseases, Brigham & Women’s College, Harvard Institute of Medicine, researchers modified the first procedure. Concluding that the meningoenchaphalitis which occurred in some patients was caused by autoimmune T-cell activation, the researchers hoped to develop a vaccine that could minimize this T-cell activation while retaining the production of Aß antibodies.

To accomplish this they created an oral vaccine that attached Aß DNA to an adeno-associated virus vector, which served to mitigate T-cell activation. Thus they were able to decrease Aß levels in the brains of the mice and yet not activate T-cells to the degree they had before, greatly reducing the risk of meningoencephalitis.

In the other new study, conducted at the University of Illinois at Chicago, researchers succeeded in making the passive immunity protocol much safer. This they accomplished by changing the point of entry for the Aß antibodies. Rather than injecting the antibodies into the body of the mice, as was done previously, antibody was injected directly into the brain of the mice. Because the antibodies were injected directly into the brain, smaller doses were needed, and side effects were minimized.

The results of the above studies, and the potential for further optimized immunization strategies may prove to be watershed events in the history of Alzheimer’s treatment.

Covance is a leading provider of innovative antibody products and custom antibody development services to the research community for Alzheimer’s disease. Visit www.Covance.com for more in-depth information and to view the suite of products for Alzheimer’s disease. Boris Predovich is Vice President of Immunology and Surgical Services at Covance Research Products.

Notes

1. J.A. Hardy, G.A. Higgins (1992), Science, 256:184-5.
2. M.P. Lambert et al (1998), Proc Natl Acad Sci, 95:6448-53.
3. D.M. Walsh et al (2002), Nature, 416:535-9.
4. Neelima B. Chauhan et al (2004), Journal of Neuroscience Research, 78, 5:732-741.
Hideo Hara et al (2004), Journal of Alzheimer’s Disease, 6, 5:483-488.