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Human Memory, Alzheimer's Disease and Drugs in Development

What is Alzheimer's Disease?

Alzheimer's Disease is one type of dementia (problem with the brain), hence, it is sometimes referred as Dementia of Alzheimer's Type (DAT). Although DAT is more common occurring with older people showing symptoms of memory and other cognitive function impairment (age-associated memory impairment) and progressively developed to become helpless , we have learned that people can develop mild cognitive impairment (MCI) at younger age (50 or younger). It is best to treat the symptoms early rather than regarding them as a result of normal aging process. As we will discuss below, medical research has made significant progress and brought hope to be able to treat memory impairment early not just to delay or slow down the deterioration.   

How Are The Memory Impairment Diseases Defined?

There are a number terms for describing the various types of memory impairment diseases. As we gain more knowledge on how brain works and how memory is impaired, we will have a better handle in defining the diseases and their treatments more precisely. The following are terms often used to describe diseases associated with memory impairment:

Alzheimer's Disease (AD) or Dementia of Alzheimer Type (DAT):  The common symptom is loss of memory. The impairment is onset at an old age typified by inflammation in the brain and gradually gets worse till not able to function as a living being. AD is named after Dr. Alois Alzheimer, a German doctor. In 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual mental illness. He found abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now called neurofibrillary tangles). Today, these plaques and tangles in the brain are considered signs of AD. Age and Family history are two risk factors for AD. Familial AD, a rare form of AD that usually occurs between the ages of 30 and 60, is inherited. However, in the more common form of AD, which occurs later in life, no obvious inheritance pattern is seen. One risk factor for this type of AD is a gene that makes a protein called apolipoprotein E (apoE). Everyone has apoE, which helps carry cholesterol in the blood. The apoE gene has three forms. One seems to protect a person from AD, and another seems to make a person more likely to develop the disease. It is likely that other genes also may increase the risk of AD or protect against AD, but they remain to be discovered.

Mild Cognitive Impairment (MCI): The common symptom is short-term memory lapses. The condition does not interfere seriously with daily living, however, there are estimated about 8 million Americans over age 50 who suffer from MCI. (not to be confused with telecommunication company MCI which has caused lots of people suffering in financial losses) According to statistics, every year 15% of people diagnosed with MCI will eventually develop Alzheimer's Disease.

Amnestic MCI (aMCI): Individuals who do not meet criteria for dementia but who will develop diagnosable dementia at high rates over the next several years.

Age-Associated Memory Impairment (AAMI):  The mild disturbance in memory function that occurs normally with aging.  Characterized by temporary memory lapses in otherwise healthy individuals, AAMI may actually affect up to 144 million Americans. A new national survey released in 2001 of people age 40 and over who have recently experienced forgetfulness reflects the high prevalence of AAMI; 61 percent of respondents admit their memory is worse than it was 10 years ago. This does sound normal except when memory impairment is progressed to the above definitions.

What Are the Symptoms of AD?

AD begins slowly. At first, the only symptom may be mild forgetfulness. In this stage, people may have trouble remembering recent events, activities, or the names of familiar people or things. They may not be able to solve simple math problems. Such difficulties may be a bother, but usually they are not serious enough to cause alarm.

However, as the disease goes on, symptoms are more easily noticed and become serious enough to cause people with AD or their family members to seek medical help. For example, people in the middle stages of AD may forget how to do simple tasks, like brushing their teeth or combing their hair. They can no longer think clearly. They begin to have problems speaking, understanding, reading, or writing. Later on, people with AD may become anxious or aggressive, or wander away from home. Eventually, patients need total care.

How is AD Diagnosed?


An early, accurate diagnosis of AD helps patients and their families plan for the future. It gives them time to discuss care while the patient can still take part in making decisions. Early diagnosis also offers the best chance to treat the symptoms of the disease.

Today, the only definite way to diagnose AD is to find out whether there are plaques and tangles in brain tissue. To look at brain tissue, however, doctors must wait until they do an autopsy, which is an examination of the body done after a person dies. Therefore, doctors can only make a diagnosis of "possible" or "probable" AD while the person is still alive.

At specialized centers, doctors can diagnose AD correctly up to 90 percent of the time. Doctors use several tools to diagnose "probable" AD, including:

These test results help the doctor find other possible causes of the person's symptoms. For example, thyroid problems, drug reactions, depression, brain tumors, and blood vessel disease in the brain can cause AD-like symptoms. Some of these other conditions can be treated successfully.

Recently, scientists have focused on mild cognitive impairment (MCI), which is different from both AD and normal age-related memory change. People with MCI have ongoing memory problems, but they do not have other losses like confusion, attention problems, and difficulty with language. Scientists funded by the National Institute on Aging (NIA) are studying information collected from the Memory Impairment Study to learn whether early diagnosis and treatment of MCI might prevent or slow further memory loss, including the development of AD.

How is AD Treated?

AD is a slow disease, starting with mild memory problems and ending with severe brain damage. The course the disease takes and how fast changes occur vary from person to person. On average, AD patients live from 8 to 10 years after they are diagnosed, though the disease can last for as many as 20 years.

No treatment can stop AD. However, for some people in the early and middle stages of the disease, the drugs tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), or galantamine (Reminyl) may help prevent some symptoms from becoming worse for a limited time. Also, some medicines may help control behavioral symptoms of AD such as sleeplessness, agitation, wandering, anxiety, and depression. Treating these symptoms often makes patients more comfortable and makes their care easier for caregivers.

Developing new treatments for AD is an active area of research. Scientists are testing a number of drugs to see if they prevent AD, slow the disease, or help reduce symptoms.

There is evidence that inflammation in the brain may contribute to AD damage. Some scientists believe that drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) might help slow the progression of AD, although recent studies of two of these drugs, rofecoxib (Vioxx) and naproxen (Aleve), have shown that they did not delay the progression of AD in people who already have the disease. Scientists are now testing other NSAIDs to find out if they can slow the onset of the disease.

Research has shown that vitamin E slows the progress of some consequences of AD by about 7 months. Scientists now are studying vitamin E to learn whether it can prevent or delay AD in patients with MCI.

Recent research suggests that ginkgo biloba may be of some help in treating AD symptoms. There is no evidence that ginkgo will cure or prevent AD. Scientists now are trying to find out whether ginkgo biloba can delay or prevent dementia in older people. (According to the Business Week, the annual sales of ginkgo is $500M, a very significant business) 

Research also is under way to see if estrogen reduces the risk of AD or slows the disease. One study showed that estrogen does not slow the progression of already diagnosed disease, but more research is needed to find out if it may play another role. For example, scientists now are trying to find out whether estrogen can prevent development of AD in women with a family history of the disease.

How Does Human Brain (Memory) Work?

In order to appreciate what medical research has accomplished in the area of developing drugs for treating memory impairment, first we need to understand how does human memory work according to scientific findings. However, due to the complexity of human brain (physical structure, functional mechanism and neurological-psychophysical behavior), there are huge amount of work devoted to the science of human brain. Therefore, it is difficult to describe human brain in a few sentences. In answering the question how does human brain (memory) work, we will only introduce the basic concepts and terms to facilitate the comprehension of the discussion to follow on drugs for treating memory impairment. A number of online references is cited for readers to get more in-depth understanding of the human brain.

Dr. Henk Haarmann (  www.bsos.umd.edu/hesp/hesp602/slides/Memory.pdf  ) has given a set of nice slides on the description of Memory. Memory is defined in three categories: 1. sensory memory 2. working memory (WM) and its storage component, short term memory (STM) and 3. long term memory.  Sensory memory deals with pre-categorized sensory codes, iconic (visual, primary visual cortex)  memory - persistent light flash and echoic (auditory, primary audio cortex) memory with characteristics of short duration (seconds), large capacity and partial report vs full report. Short term memory deals with visual-spatial, phonological loop, semantic STM, central attention and individual difference. Working memory deals with storage (STM) and processing on daily tasks and activating LTM. Long term memory deals with declarative memory (explicit, facts, episodic and semantic) and non-declarative (implicit, procedural (skill and habit), priming and conditioning) with characteristics of very large storage capacity and very long term storage (may fail to retrieve due to proactive and retroactive interference from information stored in other parts of LTM). The long term potentiation (LTP) is the learning/memory mechanism performed at the cell-memberine level and demonstrated in the hyppocampus and other areas of the brain.

On the subject of memory, another short description published on the web site of Instituto de Fisiologia Celular is very well written which is a part of the introduction of the brain ( ifcsun1.ifisiol.unam.mx/Brain/memory.htm ) The memory section is quoted below: (7 Paragraphs in bold)

MEMORY

Memory is the process by which a learning experience is retained over time. A single memory can be retrieved several times when the proper stimulus is presented. There is no consensus on the way in which to classify memory, but two dichotomies often arise when studied by neuroscientists. The first dichotomy is between procedural and declarative memory, and the second dichotomy is between short term memory and long term memory.


Procedural memory in humans is related to the knowledge of rules of action and procedures, which can become quite automatic with repetition. When one studies a learning curve of some task, we can see that performance is improved (either by less errors or quicker responses, or by a combination of both) with the number of repetitions of that task. Having a lot or little "practice" with certain task is procedural knowledge. Nonassociative learning and most classical conditionings produce procedural memory.


Declarative memory involves explicit information about facts. To remember one's telephone number, or the names of the parts of the neuron, does not require a set of rules or procedures, it is explicit and involves associations with other events. To put it colloquially, declarative memory is what we know consciously, and procedural memory is what we perform unconsciously. Although this dichotomy was first put forward for describing human memory, it is useful for classifying animal memory as well. A rat can improve on the performance in climbing a small ladder (procedural) and can remember if there will be food on top or not (declarative) if a light is tuned on or off.


Although this division of memory seems arbitrary at first, it is very useful in neuroscience since each type of memory probably has different types of neural substrates. For instance, the hippocampus and temporal cortex seem to be involved in the formation of declarative memory, but not of procedural memory. Whereas certain nuclei of the cerebellum and spinal chord seem to be necessary for procedural memories to form, but do not intervene in declarative memory. Due to this anatomical organization, declarative memory is said to be controlled by higher brain mechanisms, while procedural memory appears to depend on lower regions and systems.


The second recurring dichotomy in the study of memory in neuroscience, is between a short lasting stage and a long lasting stage. The short stage is called short term memory (STM) an is defined by its limited capacity and lability, since it usually only contains a few (less than seven) pieces of information, and can be disrupted easily with either strong or distracting stimuli, or with brain manipulations. If STM goes undisturbed, is only lasts from a few seconds up to several hours, depending on the type of learning and the organism involved.




Long term memory (LTM) occurs when the information is kept for longer periods, up to the whole lifetime of the organism. This occurs less often and only with association of stimuli that is relevant to the organism, either because of a biological predisposition or by continuous repetition. Usually experiences charged with a strong affective component (either reinforcing or aversive) tend to go into long term memory more often than others. This type of memory is less labile, and is not easily disrupted. The most frequent reason that some information cannot be retrieved from LTM, is a retrieval problem itself, and not that the memory is lost, since it can appear later in another context. Very few restricted lesions have an effect on LTM, but some magor afflictions like hypoxia (lack of oxygen in the brain), trauma or electroconvulsive shock can disturb long term memories that were stored. However, most memories come back in time, and the ones that do not were the memories most recently learned before the trauma or treatment. This lack of lability of LTM suggests that the brain (particularly neurons) go thru plastic changes that are almost permanent. In the case of STM, the changes probably involve just the way some neurons function, but not the plastic permanent changes.


On the neural level, a notable difference between the dichotomy between procedural and declarative memory, and the dichotomy between STM and LTM, is that in the latter there seems to be involved either higher and lower brain structures, and in some cases the same anatomical area is necessary for both STM and LTM. It is the neural mechanisms involved that are the difference underlying each.
               ifcsun1.ifisiol.unam.mx/Brain/memory.htm 

The neurological model of the brain although incomplete is representing a good understanding of how brain functions. The human brain has at least 100 billion neurons, brain cells, and 100 trillion synapses, cell connectors with a processing center deep in the brain called Hippocampus. When a memory process takes place, a cascade of brain chemicals called neurotransmitters is released. These transmitters are messengers carrying information across the synapses and delivering to the appropriate area of the brain for storage. The stronger the memory the more the synapses are created. Eventually, a group of neurons connect together to form a long term storage space for information. This process can take hours even days.   

In recent years of neuro-biological studies of brains (memory) have made very significant strides. Prof. Eric R. Kandel at Columbia University, a Nobel Laureate (2000), who studied the brain of sea slug, has discovered that a neurotransmitter called cyclic-AMP, cAMP, plays a key role in strengthening synapses. cAMP activates a protein called CREB which in turn switches on the genes that control the release of neurotransmitter essential to long term memory. Dr. Kandel has formed a company, Memory Pharmaceuticals Corp., and has received venture funding of $150M to produce drugs that can block the breakdown of cAMP. 

A study  published in 2002 in Annals of Neurology by Steven T. DeKosky, M.D., professor of neurology, psychiatry, neurobiology and human genetics at the University of Pittsburgh School of Medicine, found that in older people with MCI, the brain produces more choline acetyltransferase (ChAT), an enzyme that is important in memory and cognitive functions. The researchers believe this is the brain’s attempt to maintain normal function as the neurons that form communication lines to the brain’s memory center die. Strengthening their finding are autopsy results showing more than 60 percent of people who had MCI within a year before they died already had evidence of neuro-degeneration that is seen in the early stages of AD. The results are almost the opposite of what most researchers believed – that a decrease in ChAT levels causes MCI – the theory behind today’s most popular Alzheimer’s treatments, which include drugs meant to boost levels of the enzyme’s product, the neurotransmitter acetylcholine (ACh).

“Because we thought deficits in ChAT were responsible for memory problems in patients with MCI, the most common treatment we use is a class of drugs called cholinesterase inhibitors that help the brain produce more. These results suggest that the brain increases production of ChAT on its own in people with MCI and that in addition to their use in early AD, these drugs may be effective if used in patients who have a deficit in ChAT – those with advanced AD." Said Dr. DeKosky. “These findings suggest we should spend more time researching ways to slow down or stop the early stages of neuro-degeneration,” added Dr. DeKosky.

Drugs for Treating Memory Impairment

In November 2002, Prof. Gary Lynch of Department of Psychiatry, University of California at Irvine published a review paper, entitled, 'Memory Enhancement: The Search for Mechanism-Based Drugs'  (Nature Neuroscience, November 2002 Volume 5 Supplement pp 1035 - 1038). This paper contains a nice figure (Fig. 1) which describes the targets for the development of memory enhancement drugs. Production of stable synaptic changes is typically divided into induction, expression and consolidation phases. These relate to steps in memory formation introduced into the psychological literature with the discovery that electroconvulsive shocks applied shortly after learning erase memory. Subsequent decades of work confirmed that memory encoding involves two distinct steps: an acquisition process requiring a few seconds, followed by a series of changes that consolidate the new information against disruption and decay, which requires hours or even days. The manifestation of memory in behavior (such as recognition) constitutes a third component emerging immediately after acquisition and in advance of consolidation. LTP seems to pass through a similar sequence of stages, two of which are logical targets for mechanism-based memory drugs. 

Professor Lynch reviewed the drug for facilitating induction,  ampakines, which enhances and prolongs the synaptic currents generated. The search for positive modulators has led to a rich pharmacology and a number of promising candidates for memory therapeutics. Several companies (Cortex, Lilly, Organon, Servier) have aligned themselves with particular modulator strategies, giving the impression that a race is going on to produce an AMPA receptor–based memory drug (see Fig. 1 for explanation). He then reviewed the drug for improving consolidation where the CREB family of transcription factors has received particular attention. Multiple efforts are now underway to develop drugs that facilitate CREB's contributions to long-term memory. Under some conditions, inhibitors of the phosphodiesterase isozyme PDE-IV, which is responsible for hydrolysis of cAMP, increase CREB phosphorylation, CREB binding to DNA, and memory scores in rats. Although the clinical use of current PDE IV inhibitors is restricted by unacceptable side effects, more potent, and perhaps selective, compounds are under development. Given the ubiquitous distribution of CREB, target selectivity (brain/forebrain) will be a critical requirement for drugs acting upon it to produce cognitive effects. At least two biotechnology companies (Memory Pharmaceuticals, Helicon) are pursuing CREB-based strategies. (see references in the review articles). Helicon headed by Tim Tully of Cold Spring Harbor laboratories in Long Island has shown promising results of boosting activity of CREB in mice. Overall, the outlook for memory improvement drug development is quite bright.   
(Reference: www.nature.com/cgi-taf/DynaPage.taf?file=/ neuro/journal/v5/n11s/full/nn935.html )

Allain (Professor of Medicine, Pharmacology, Laboratory of Experimental and Clinical Pharmacology, Faculty of Medicine, avenue du Pr Léon-Bernard, 35043 Rennes cedex) and Schuck (Pharmacoepidemiologist, M.D. Laboratory of Experimental and Clinical Pharmacology, Faculty of Medicine, avenue du Pr Léon-Bernard, 35043 Rennes cedex) ( www.health.fgov.be/WHI3/Hub/hub1/Drugs.htm ) have also reviewed the drug development for brain (memory) improvement. They have classified and discussed four generations of drugs, namely, 

          www.health.fgov.be/WHI3/Hub/hub1/Drugs.htm

Natural Ways of Maintaining Memory Function

There are 4-4.5M DAT patients in US (50% over 85 has DAT). It is projected that in 2050 over 70M people will be over 65 and 13.2M of them will have DAT barring the arrival of a miracle DAT drug. With the positive outlook of the development of memory drugs, perhaps, we don't need to worry about year 2050. However, in 10 years, 77M baby boomers will be over 50 years old. Based on a current projection, 25% of (77M) will have some form of dementia. Some may have memory problem even before 40. This is not good at all. There is no assurance that the above mentioned drug development will produce a DAT curing drug or MCI prevention drug in 10 years. We can be optimistic that government will pump more research funding into accelerating the bioscience research related to brain. We can be also optimistic about the commercial interest and competition in accelerating the memory drug development since the 'market' is enormous (Government spends 100B for caring AD patients in 2002-3). But are we going to be optimistic about the drug price being affordable by average citizens in ten-year time? probably not! I won't bet on it!

It is perhaps wise to pay attention to some natural ways of preventing the early MCI or other form of dementia. One established fact is that more brain stimulation in the young age will strengthen the brain to prevent early development of MCI or DAT. Perhaps you have heard about people telling you the piano lesson and multiple language studies are good for young people. In fact, brain activity is good even for old age. That is the reason we heard doctors say, 'if you don't use it you will lose it'. (Some social health studies have proven this). 

The second fact is that fatty diet is not good for the brain. The plaque found in the DAT patients when they die have some similarity to the plague formed in the arteries due to high cholesterol diet. Currently there are studies about whether the cholesterol medicine such as lipitor and Zocor can slow memory loss or not. Other studies are being conducted about the effect of vitamin E, estrogen, certain herbs, even curry (DAT rate is low in India) on human memory.

It does not take high intelligence to conclude that it will be extremely beneficial to yourself and everyone around you if you adopt a healthy (less fatty) diet and engage a lot of brain stimulating activities. To help my readers to get started, I am listing here a number of websites which provide brain stimulating games for all ages. If what you do now can delay a few years of getting any brain or memory disease, you will be doing yourself a great favor. The extra few years may mean that an affordable drug will become available to you so you will never suffer from DAT.

Here are the web sites, including one game I invented for the very purpose of stimulating brain activities which I named it BRAINO Scrammble. Braino has three games in one absorbing the merits of the three most popular games in the world, that is, Scrabble, Poker and Ma-Jong.

Games for Improving Memory and Brain Function

1. From NASA: http://olias.arc.nasa.gov/cognition/tutorials/index.html

2. From Pat's Page: http://www.exo.net/jaxxx/activitymemory.html#anchor29455

3. Fun Game with Kids: http://www.funbrain.com/cgi-bin/fm.cgi

4. from Queendom: http://www.queendom.com/mindgames/index.html

5. Braino or Scrammble Invented by Dr. Chang: http://www.mi-card.com/magic/scrammbleorder.html

Related article by Dr. Chang: Schizophrenia, Olanzapine (Zyprexa) and Risperidone (Resperdal)

In Conclusion, Let's Use Our Brains and Have Some Fun! 

 

Written by Ifay Chang, Ph.D. on August 24, 2003

Dr. Chang is the co-founder of Medical World Search which offers an intelligent medical search engine, called MWSearch. MWSearch is an independent search service without affiliation with any healthcare organization or drug companies. Medical World Search ( www.mwsearch.com ) has been offered for public use since 1996.

In early 90's, while working as a research scientist at IBM T. J. Watson Research Center, Dr. Chang led a group of researchers developing an advanced clinic information system with the purpose of supporting efficient and reliable healthcare practice. The system has been adopted by Kaiser Permanente and other healthcare organizations. Dr. Chang writes articles for MWSearch from time to time.

This article is copyrighted but you may use it or reproduce it in part or in whole with proper acknowledgement made. The author can be reached at ifay@mwsearch.com


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