Source:Society For Neuroscience
Date:2003-01-08

Lowering Beta-Amyloid Levels In Blood To Treatment Alzheimer's
WASHINGTON, D.C. January 7 - Agents that alter blood levels of beta-amyloid protein in mouse models of Alzheimer's disease represent a potential approach to treating the illness in humans that may be safer than the vaccine method of therapy, researchers report in a new study.

Beta-amyloid protein is a component of the amyloid plaques that accumulate in the brains of people with Alzheimer's disease. Beta-amyloid is viewed by many researchers and clinicians as the underlying cause of the degeneration and dementia that characterize the illness. Alzheimer's disease is a progressive, degenerative brain disease and the most common form of dementia. There is no cure. Approximately four million Americans have the disease and some 14 million are expected to have it by 2050 unless a cure or preventive treatment is found.

"Recent evidence suggests that this protein in the peripheral circulation outside the brain may contribute to its accumulation in the brain," says study co-author Karen Duff, PhD, of the Center for Dementia Research, Nathan Kline Institute/New York University. The study, funded by the National Institutes of Health and the Alzheimer's Association, appears in the January 1 issue of The Journal of Neuroscience.

If Alzheimer's disease can effectively be treated by agents that do not need to enter the brain, pharmaceutical companies may be able to develop targeted drugs that have few effects on the central nervous system, she adds. Previous animal studies suggested that one way to do this was through a vaccine that produced antibodies to amyloid. But Elan Corporation and American Home Products ended trials of their immune-based Alzheimer's vaccine in February 2002 after 15 patients experienced swelling of the central nervous system.

"There's good medical precedent seen in the treatment of coronary heart disease by administering agents that lower serum cholesterol levels," notes Bradley Hyman, MD, PhD, a neurologist at Massachusetts General Hospital in Boston. "This kind of parallel approach ¨C blocking beta-amyloid accumulation in the brain by binding it to an agent in the bloodstream ¨C represents an extremely viable line of research."

Rest here.

ces

I can speak to this from first hand experience. Prior to taking Aricept, Mom was experiencing many typical AD symoptoms. Fuzzy thinking, memory loss, paranoia, hallucinations etc. When she began taking Aricept there was noticeable improvement in 3 days.

Keep in mind this is only my experience with this drug.

Vicki

Sugarlips

Alzheimer's Drugs Relieve Several Symptoms
Tue Jan 7, 5:41 PM ET Add Health - Reuters to My Yahoo!

By Merritt McKinney

NEW YORK (Reuters Health) - Drugs used to preserve memory and intelligence in people with mild to moderate Alzheimer's disease may provide other benefits as well, according to a new report.

In a review of clinical trials, drugs called cholinesterase inhibitors seemed to improve psychiatric symptoms, such as hallucinations and paranoia, which often affect people with Alzheimer's. In addition, the drugs, which are the only medications approved in the US to treat the memory-robbing disease, also seemed to help people with Alzheimer's maintain their daily activities longer than people who did not take the medications.

The findings are published in the January 8th issue of the Journal of the American Medical Association.

"These drugs, which are underutilized in general, most likely because many docs question how helpful they are, may have another role" in the treatment of Alzheimer's disease, Dr. Kristine Yaffe, the study's lead author, told Reuters Health.

Rest here.

ces

Have you noticed that your lead post in this thread says:
News and Research Updates on Parkinson's Disease.

Feel free to delete this post

ces

Stunted Brain Protein Seen as Causing Cell Death

By Malcolm Ritter
The Associated Press

Dec. 8 — Scientists have found another potential clue to understanding what goes wrong in the brain to cause Alzheimer’s disease. The work, while preliminary, suggests a possible new approach to treatment.

Researchers focused on a crucial enzyme in brain cells and a protein that controls its activity. Their findings suggest that if brain cells produce an abnormal, stunted version of this protein, the enzyme can run amok, leading to death of brain cells. That could play a role in causing Alzheimer’s.
Scientists found the shortened protein in the autopsied brains of Alzheimer patients. In test-tube studies, the stunted version made the enzyme overactive, killing rat brain cells.
Untangling the Tangles
The work could help explain why certain cells in Alzheimer brains typically contain abnormal protein tangles. These tangles, along with protein deposits called plaques, are hallmarks of the disease. Scientists are trying to figure out what roles the tangles and the plaques each play in causing Alzheimer’s.
The new work is reported in Thursday’s issue of the journal Nature by a team including Li-Huei Tsai, an associate pathology professor at Harvard Medical School and a researcher at the Howard Hughes Medical Institute.
She said scientists might be able to develop new treatments if they can figure out how to block production of the stunted protein or keep the enzyme under control.
John Trojanowski, who studies Alzheimer’s at the University of Pennsylvania, said the work suggests a new direction for research.
The study describes a story with three main actors: the normal protein p35, the stunted version p25, and the enzyme Cdk5.

Rest here.

ces

Rotterdam Study Questions Links Between Fat and Dementia Risk
by Hakon Heimer
(c) Alzheimer Research Forum

24 December 2002. In conflict with a number of recent studies, six-year data from the Rotterdam study of aging failed to show a link between dietary fat and risk of dementia. The results are reported in today’s Neurology.

Drawing on disparate lines of evidence, some researchers have been building a case that dietary fat intake affects dementia risk. For example, higher dietary cholesterol increased cerebral Ab deposition in some animal experiments, and certain polyunsaturated fats may have antiinflammatory properties, which might counteract the alleged inflammatory contribution to dementia. Some, but not all, epidemiologic studies have linked higher serum levels of cholesterol (mostly during midlife) with higher dementia risk, and cholesterol-lowering drugs such as statins appear to reduce the risk of Alzheimer's dementia. Indeed, earlier results from the Rotterdam study have contributed to this theory (see Kalmijn et al., 1997), finding that high intake of total fat and low intake of fish (with its high levels of cis n-3 polyunsaturated fatty acids) were significantly associated with risk of dementia at the two-year follow-up in the Rotterdam study.

Now Monique Breteler and her colleagues in the Netherlands at the Erasmus Medical Center and at the University of Utrecht report the findings of six years of follow-up in the study of elderly residents (55 years or older at baseline) of a suburb of Rotterdam. Of the 5,395 subjects whose baseline and follow-up exams included complete dietary data, 197 (seven percent) had developed dementia (146 with AD; 29 with vascular dementia; and 22 with other dementias).

The researchers found no contribution to dementia risk from the intake of total fat, saturated fatty acids, or trans-unsaturated fatty acids, or from dietary cholesterol (adjusted for age, gender, total energy intake, and vitamin E intake). Conversely, dietary intake of the so-called "good" fatty acids, the cis mono- or polyunsaturated fatty acids, failed to reduce AD risk. These findings held true for all dementias, vascular dementia, and AD, and when additional lifestyle elements were factored in (e.g., smoking, alcohol, fruit and vegetables, dietary supplements, body mass index). Similarly, excluding patients using lipid-lowering drugs, or those with myocardial infarction or diabetes, did not change the results.

"Given the limited number of studies on fat intake and risk of dementia, we think it is premature to conclude from our observational study that cholesterol or cholesterol-affecting fats are not associated with risk of dementia or its subtypes. Larger, prospective studies with longer follow-up periods are needed to confirm our findings," the authors caution in their conclusion.—Hakon Heimer.

References:
Englehart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JCM, Breteler MMB. Diet and risk of dementia: Does fat matter? Neurol. 2002;59:1915-21.

Several relevant links and discussion items are located on the Alzheimer Research Forum Website.

Proteins are the substances most responsible for the daily functioning of living organisms. Destruction to proteins can be caused by oxidation (as by free radicals) and protein-sugar reactions (glycation). Once too many proteins lose their ability to function, the body becomes prone to degenerative diseases and premature aging.1 Carnosine, an amino acid compound, has been shown to specifically protect against the age-related degradation of protein.

Carnosine quenches the most destructive protein-oxidizing agent (the hydroxyl radical). One study showed carnosine was the only antioxidant to significantly protect cellular chromosomes from oxidative damage.2 Antioxidants cannot completely protect proteins. Nature's second line of defense is to repair or remove damaged proteins.3 This is where carnosine demonstrates its most profound anti-aging effect.

Protein degradation occurs as a result of cross-linking and the formation of advanced glycation end products (AGE). These changes figure prominently in the processes of aging and its typical signs such as skin wrinkling and brain degeneration.4,5 Studies show that carnosine is effective against cross-linking and the formation of advanced glycation end products (AGE).6,7 Glycated proteins produce 50-fold more free radicals than nonglycated proteins and carnosine may be the most effective anti-glycating agent known.

An example of carnosine's defense against protein degradation is provided by MDA (malondialdehyde).8 MDA causes protein cross-linking and AGE formation. Carnosine has been shown to inhibit MDA-induced glycation in blood albumin and eye lens protein.9 Carnosine has also been shown to keep MDA from inducing protein cross-linking.10 One study showed that carnosine actually decreased MDA levels in mice.

Carnosine is highly concentrated in the brain. The reason is that the brain uses carnosine to protect against cross-linking, glycation, excitotoxicity and oxidation. Animal studies show that carnosine provides broad protective effects in simulated ischemic stroke.11

Abnormal copper and zinc metabolism stimulates senile plaque formation in Alzheimer's disease. Chelators of these metals dissolve plaques in the laboratory. Carnosine is a potent copper-zinc chelating agent that can inhibit the cross-linking of amyloid-beta that leads to brain cell plaque formation. A signature of Alzheimer's disease is impairment of brain arterial and capillary system. Carnosine has been shown to protect the cells that line brain blood vessels from damage by amyloid-beta as well as byproducts of lipid oxidation and alcohol metabolism.12

Rest here, 2 pages.

I've decided to start both Mom and myself on carnosine. This is after reading on it for awhile, not a snap decision.

ces

A total of 10 posters were presented at the meeting on T-588, Toyama Chemical Co Ltd's phase II drug for the potential treatment of neurodegenerative diseases. The drug protects cultured microglia against b-amyloid peptide-induced cell toxicity, it also protects astrocytes from reperfusion- and H2O2-induced apoptosis via activation of the ERK pathway. <<< That's from a 1999 article. If it was in phase II back then, where is it now??? Found that here which doesn't tell you anymore than that paragraph above.

Found another article here. And the "current status" of T-588 is a bit unclear to me. Since at the top of the article you see these 2 dates, 2000 and 2003:

2 January 2003

Alzheimer's Disease: An Update
Drug and Market Development (15 April 2000)

As reported in Drug & Market Development Newsletter as recently as January 2000, Alzheimer's disease (AD) continues to be an affliction for which an effective therapy has been hard to pin down. Still, with some four million Americans (and as many as 14 million, including milder forms) suffering from AD, and with the cost of providing treatment and daily care to patients reaching $90-120 billion per year, researchers continue to strive for the key target for treatment or prevention.

Beta-amyloid deposits, neuritic plaques, and neurofibrillary tangles are most strongly linked to AD, especially as prospective targets for future therapy. Decreased amounts of acetylcholine are also a characteristic of AD. What follows is an update on current research in AD.

The significance of genetic links to AD, including apolipoprotein E4 (ApoE4), deserves special attention for the clues they will provide toward prevention and treatment of AD. ApoE4 has already been used in trials to determine subsets of patients likely to respond to particular drugs in development.

Beta-Amyloid

Beta-amyloid is an insoluble polypeptide with adverse effects thought to result from free radicals that cause oxidative stress and lead to neuronal damage. Among the theories for addressing AD is to use free radical scavenging agents to limit the damage caused by free radicals created through beta-amyloid.

Compounds of this type include idebenone (Takeda Chemical Industries; Osaka, Japan), which is both a free radical scavenger and a stimulant of certain nerve growth factors. Early studies indicated that idebenone may have value in the treatment of mild dementia, but although licensees Glaxo Wellcome (Middlesex, UK) and American Home Products (Madison, NJ) launched the drug in several countries, it has been withdrawn in Japan and Phase III trials have been discontinued.

Sue Griffin of the Geriatric Research, Education, and Clinical Center at the McClellan Veterans Affairs Medical Center (North Little Rock, AR) and the Geriatric Department at the University of Arkansas for Medical Sciences (Little Rock, AR) recently noted research that examined factors that stress or injure neurons. According to Griffin, stress increases the synthesis and translation of beta-amyloid precursor protein, which in turn leads to increased secretion of amyloidogenic fragments. Furthermore, this process prompts microglia to create interleukin-1, which drives further beta-amyloid precursor protein production, activates astrocytes, and induces expression of S-100beta, which promotes the growth of neurites. Griffin reports that vitamin E can inhibit microglia activity and thus production of interleukin-1.

In the January 7, 2000, Nature researchers from Harvard Medical School (Boston, MA) and BioDesign Research Group (Saitama, Japan) revealed that they have uncovered a novel mechanism by which cells die involving the endoplasmic reticulum (ER) and caspase-12. Importantly, the collaborative work also establishes a direct connection between caspase-12 and AD, providing a significant new lead toward potential treatments for the disease. Junying Yuan and colleagues focused their research on clarifying the specific function of caspase-12. Surprisingly, they found that the caspase was located in the ER, which is also where the beta-amyloid precursor resides. In theory, a caspase-12 inhibitor could potentially prevent beta-amyloid-induced apoptosis, a major factor in AD-related neurodegeneration.

Neuritic Plaque

The development of neuritic plaque is also, in part, associated with inflammation. Therefore, anti-inflammatory drugs may lead to a new therapeutic venue. Some studies have linked a decreased risk of AD among users of NSAIDs (non-steroidal anti-inflammatory drugs), but there have as yet been few randomized trials to test this. Adverse gastrointestinal effects are hallmark of some anti-inflammatory drugs, which would be problematic for elderly patients, but there are now trials underway testing the possible role of the less toxic cyclooxygenase-2 (COX-2) inhibitors in AD patients and people at risk for AD.

Acetylcholinesterase Inhibitors

Acetylcholinesterase inhibitors include physostigmine (Synapton®; Forest Laboratories; New York, NY), tacrine (Cognex®; Parke-Davis; Morris Plains, NJ), donepezil (Aricept®, Pfizer/Eisai; New York, NY/Tokyo, Japan), metrifonate (Bayer; Leverkusen, Germany), and rivastigmine (Exelon®; Novartis; Basel, Switzerland). These compounds increase the concentration of acetylcholine and the duration of its action in synapses by inhibiting the acetylcholinesterase enzyme.

Tacrine, the first cholinesterase inhibitor to receive FDA approval for use in patients with AD, nonetheless provides only modest improvements in cognition, has a lower bioavailability than rivastigmine and donepezil, and it has a worse side-effect profile. In Phase II and III trials, donepezil significantly improved cognition and reduced the severity of the disease when compared with placebo. Unlike tacrine, donepezil is not hepatotoxic and is more tolerable. Rivastigmine matches or exceeds its peers in the improvement experienced by patients, but requires a longer period of titration than donepezil before a therapeutic dose is attained.

On March 1, 2000, Sanochemia Pharmazeutika AG (Vienna, Austria) announced the first European registration of its acetylcholinase inhibitor, Reminyl (galantamine; formerly known as SPH-1286). The approval came from Sweden; Reminyl will now be submitted through the EU Mutual Recognition Procedure to gain marketing approval throughout Europe.

NeuroSearch (Ballerup, Denmark) recently selected NS2330 for clinical development. NS2330 increases the activity of dopamine and noradrenaline through an uptake inhibition mechanism that also increases the release of acetylcholine in areas of the brain involved in cognitive function. Since the function of all three neurotransmitters is affected in AD, NeuroSearch expects that NS2330 will have a greater therapeutic effect on patients suffering from AD than compounds that solely increase acetylcholine function. Phase I trials have been completed, and the FDA has granted NeuroSearch approval to commence Phase II trials.

Other compounds being tested include xanomeline (Novo Nordisk/Eli Lilly; Bagsvaerd, Denmark/Indianapolis, IN), besperidine (Hoechst Marion Roussel; Frankfurt, Germany), and talsaclidine (Boehringer Ingelheim/Pharmacia & Upjohn; Ingelheim, Germany/Peapack, NJ).

Other Mechanisms

Some studies have suggested that estrogen replacement therapy may significantly delay the onset of AD in women and lower their risk of developing it at all. Several small trials found that estrogen treatment improved cognition. Estrogen's ability to act both as an antioxidant and as an anti-inflammatory may explain this risk reduction, but estrogen also boosts acetylcholine, may promote growth and survival of neurons, and may reduce the creation of beta-amyloid by affecting its precursor protein. Additional studies, however, will be required to prove any connection between estrogen therapy and the risk of AD in women.

In the second quarter of 2000, Toyama Chemical (Tokyo, Japan) expects to begin Phase II trials in Britain of T-588, and may also shortly begin tests of the drug in the US. In collaboration with New York University (New York, NY), Toyama found that T-588 demonstrated an ability to protect nerve cells in the brain.

ces

Edited to add, T-588 is also planned for ALS trials.

Protocol Number: 97-N-0049

Title: Tolerability and Primary Efficacy of CX516 in Alzheimer's Disease
Number: 97-N-0049
Summary: Glutamate is an amino acid released by brain cells that acts to excite other cells. Glutamate attaches to special sites on cells called AMPA (alpha-amino-2,3-dihydro-5 methyl 3-oxo-4-isoxazolepropanoic acid) receptors. The brain cells responsible for releasing glutamate are damaged in Alzheimer's disease and other conditions affecting thinking and reasoning.

Researchers would like to see if giving patients a drug that attaches to AMPA receptors improves the symptoms of Alzheimer's disease.

CX516 (Ampalex) is a test drug that affects the AMPA receptors. This study will investigate the effectiveness and safety of CX516 on patients with Alzheimer's disease.

Patients will be given capsules of CX516 for up to 28 days in different amounts. The effectiveness of the drug will be measured by neurological tests, safety will be monitored by frequent check-ups and lab examinations.

Sponsoring Institute:
National Institute of Neurological Disorders and Stroke (NINDS)
Recruitment Detail
Type: Active Accrual Of New Subjects
Gender: Male & Female
Referral Letter Required: No
Population Exclusion(s): None

Eligibility Criteria:
INCLUSION CRITERIA:

Study subjects will satisfy NINCDS-ADRDA criteria for probable Alzheimer's disease, although other dementing disorders may be included if they are also neurodegenerative in nature. Dementia severity will be in the mild to moderate range (mini-mental status examination total score between 15 and 26, inclusive). The modified Hachinski Ischemia Score must be less than 4, and brain MRI performed within 15 months of enrollment must be compatible with the diagnosis of neurodegenerative disease or Alzheimer's disease.

No one will be excluded or discriminated against based on the grounds of race, creed, or gender. Every attempt will be made to include women and minorities in the study population.

EXCLUSION CRITERIA:

Neurologic: Hemispheric or lacunar stroke (focal T2 hyperintensities of unknown significance are allowed), hydrocephalus, subdural hematoma, or mass lesion on neuroimaging study; "epileptiform" baseline EEG or known seizure disorder; alcoholism; head trauma with loss of consciousness concurrent with onset of dementia; chronic CNS infection (positive MHA-TP or FTA-ABS acceptable if luetic brain disease excluded by documented studies or treatment).


General Medical: Acute serious infection, including hepatitis; active or history of serious cardiac arrhythmia; uncontrolled hypertension; active or history of thyroid disease; folic acid deficiency (less than 0.9 ng/mL); vitamin B12 deficiency (less than 160 pg/mL) within one year prior to enrollment; severe renal insufficiency (creatinine clearance less than 25 mL/min, BUN greater than 40 mg/dL, or serum creatinine greater than 2.0 mg/dL); hepatic insufficiency (SGPT or SGOT greater than 3 x upper limit of normal, or total bilirubin greater than 2.0 mg/dL).

Read rest here.

Assoc'd info:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8768713&dopt=Abstract

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8153879&dopt=Abstract

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2900537&dopt=Abstract

Further Study Details:
Stimulation of neuronal alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptors is an important step in the formation of memory. Neurons that release glutamate, the natural ligand for these receptors, characteristically degenerate in Alzheimer's disease (AD) and related dementing disorders. To determine whether pharmacologic stimulation of these AMPA receptors will restore more normal cognitive function to Alzheimer-type patients, a novel AMPA receptor modulator, CX516, will be administered orally for up to twenty-eight days at various dosages. Drug-induced alterations in intellectual function, with a particular emphasis on delayed recall, will be measured by standardized neuropsychological tests. Safety will be monitored by frequent clinical assessments and laboratory tests.

ces

Alzheimer's Study Takes A New Approach
June 21, 2001
By Lisa Ellis
InteliHealth News Service

A drug that was removed from the market nearly 30 years ago appears to remove the protein deposits characteristic of Alzheimer's disease by neutralizing excess copper and zinc in the brain, according to an animal study conducted by researchers at Harvard Medical School.

This approach contrasts with the prevailing trends in Alzheimer's research, which have concentrated on eliminating the protein deposits, called beta-amyloid plaques, through use of a vaccination or other means. The Harvard researchers, on the other hand, contend that beta-amyloid accumulates into harmful deposits only because of its interaction with excess copper and zinc in the brain.

Using elderly mice that had been bred to develop Alzheimer's disease, the researchers treated them for nine weeks with clioquinol, an antibiotic. The investigators found that the drug, which neutralizes copper and zinc, reduced by half the level of deposits of beta-amyloid, a brain pathology close to the cause of Alzheimer's disease.

The study, published in the June 2001 issue of the journal Neuron, was led by Ashley I. Bush, M.D., Ph.D., along with colleagues at Massachusetts General Hospital and at medical centers in Houston, Sweden and Australia.

Although more study is needed, this approach using clioquinol may turn out to be helpful in the treatment of Alzheimer's, says Stephen Snyder, Ph.D., a research program director for the National Institute of Aging, which provided some funding for the study.

"It's too soon to say that any one approach — whether medicinal vs. vaccination, let alone the specifics of either approach — will in the long run be superior," Snyder says.

Dr. Bush, an associate professor of psychiatry at Harvard, and his colleagues initially studied the role of copper and zinc in the brains of Alzheimer's patients, which have particularly high concentrations of the metals in the beta-amyloid plaques characteristic of the disease. Both metals are essential to the body, but normally only small amounts are required and excess metals are excreted.

The researchers assumed that beta-amyloid must have some purpose, Dr. Bush says. "What we think is that this is a normal protein that becomes corrupted. Our evidence is that the protein (beta-amyloid), when it binds copper, gains a chemical property that it shouldn't have."

Through the resulting chemical process, he says, beta-amyloid converts dissolved oxygen to hydrogen peroxide, which in turn causes cell damage. Zinc released from brain tissue can neutralize this damaging process, but at the same time it induces more beta-amyloid to accumulate, which creates a "vicious cycle" of protein accumulation and cell damage, he says.

Rest here.

ces

Every second, a destructive process called “glycation” occurs throughout the body. Glycation can be described as the binding of a protein molecule to a glucose molecule resulting in the formation of damaged, non-functioning structures. Many age-related diseases such as arterial stiffening, cataract and neurological impairment are at least partially attributable to glycation. The glycation process is presently irreversible.

In the August 2001 issue of Life Extension magazine, an article reported on a compound called ALT-711 that has been shown to partially reverse glycation. Regrettably, the company trying to get ALT-711 through the FDA’s drug approval process is woefully under funded, and it may take years before this lifesaving compound becomes available…if ever.[1]

Since we cannot yet reverse the pathological effects of glycation, it becomes critical for those seeking to prevent premature aging to at least slow this lethal process.

Life Extension has long argued that the high cost of gaining FDA-approval denies Americans access to life-saving compounds such as ALT-711.[2] It can take so long for a new compound to become an approved “drug”, that many companies run out of capital before they are able to comply with the FDA’s Byzantine regulatory procedures. The result is that Americans die even though potentially effective therapies sit in the FDA’s waiting room.

Since we cannot yet reverse the pathological effects of glycation, it becomes critical for those seeking to prevent premature aging to at least slow this lethal process.

Gaining control over our biochemistry

A recent study explains how certain chemical reactions, such as glycation, are so dangerous to the body. This paper pointed out that organisms survive by successfully integrating the countless chemical reactions that sustain their metabolism. Aging results largely from the chronic insults caused by chemical side-reactions that cumulatively degrade the structure and function of the organism.[3]

The most important of these “side-reactions” are oxidation and glycation. Oxidation occurs when free radicals attack biological molecules, removing an electron—just as iron oxidizes when it rusts. The oxidation of fats, called lipid peroxidation, sets off a chain reaction that generates large numbers of free radicals. Glycation is a series of reactions that irreversibly cross-links sugars to proteins, as happens when a chicken browns in the oven.

The body’s proteins are the most important targets of these reactions. From a biochemical point of view, the body is composed mostly of amino acid chains that we know as proteins. There is a telltale biochemical sign of serious protein damage called the carbonyl group, which becomes attached to proteins in oxidation or glycation reactions. The carbonyl group is actually carbon monoxide (CO), which blocks oxygen use and transport. “Carbonylated” proteins lose their elasticity and resist the body’s attempts to break them down. Later in life, about one-third of the body’s proteins become carbonylated in this way.

How does the body cope with these chronic assaults on proteins? Long-lived cells, such as neurons and muscle cells, contain high levels of a dipeptide called carnosine, made up of histidine and beta-alanine. Unlike ordinary antioxidants, carnosine blocks all the above-mentioned pathways of protein carbonylation.

It is now known that metals, especially copper, strongly promote these carbonylation pathways. Fortunately carnosine chelates (binds) excess copper and zinc so that they cannot promote carbonyl-forming reactions.

Protein Browning

Antioxidants protect proteins against oxidative damage caused by free radicals, but not against equally damaging sugars. When sugars (or sugar-containing reactive compounds such as aldehydes) cross-link proteins, the result is wrinkled skin, neurodegeneration, atherosclerosis and diabetic complications.

The glycation process that turns a chicken brown in the oven is exactly what happens to the proteins in our body as we age. When body proteins react with sugars they turn brown and fluorescent, lose elasticity, and cross-link to form insoluble masses that generate free radicals. The resulting AGEs (advanced glycation endproducts) accumulate in our collagen and skin, cornea, brain and nervous system, arteries and vital organs as we age. Unfortunately, they are highly resistant to the normal processes of protein turnover and renewal that maintain the healthy tone of youthful body tissues and organs.

Glycation and oxidation reinforce each other in a vicious circle. Glycation has long been considered a “fixative” of free radical damage, while glycated proteins act as free radical generators. A leading glycation researcher, Professor John Baynes of the University of South Carolina, suggests that we think of glycated proteins as amplifiers and integrators of oxidative damage.[3] Copper is the accelerant, stimulating oxidation, lipid peroxidation and glycation. A study by Professor Baynes and associates soon to be published in the Journal of Biological Chemistry shows that copper chelation is instrumental to glycation fighters, including carnosine.[4]

Consequently, it is necessary to suppress all of these interrelated factors to protect the body’s proteins. While antioxidants close the front door to oxidation, they leave open the back door to glycation, and the side door to metal toxicity. Antioxidants are simply not cut out to block the many biochemical pathways that damage proteins. Indeed, research conducted by Professor Baynes and associates shows that oxidation is not necessary for protein glycation and cross-linking, from which they conclude:

Without the need for oxidation chemistry for efficient browning of proteins by smaller sugars, therapeutic strategies that rely solely on antioxidant activity to inhibit the Maillard reaction [the “browning” process that follows glycation] may have limited efficacy.[5]

Nature doesn’t rely solely upon antioxidants to protect vital proteins in the brain, eye and muscle, and neither should the Life Extensionist. Rather, nature employs a multipurpose compound that scavenges free radicals, quenches reactive aldehydes and lipid peroxidation products, inhibits glycation and chelates toxic metals. A complete review of carnosine’s properties is beyond the scope of this article, however we note that carnosine has been shown to protect DNA, crystallin (eye lens protein), amyloid beta, the cellular antioxidants SOD and catalase, serum albumin and anti-thrombin III (an anticoagulant blood protein) from glycation. For further information, see the sidebar “Carnosine Summary” and the articles cited therein.

Alzheimer’s disease

Carnosine’s ability to chelate copper and zinc is especially important in the brain. These metals are neurotoxic at far lower concentrations than previously thought, yet are essential to the transmission of impulses across brain synapses. Nature’s solution to this problem is carnosine, without which normal brain activity would be neurotoxic. Carnosine has been shown to protect neurons from copper and zinc toxicity at concentrations similar to those found in the brain.[6]

The significance of these findings is underscored by the discovery that tiny amounts of zinc and especially copper stimulate the formation of senile plaques in Alzheimer’s disease, by causing amyloid-beta to aggregate.[7] Conversely copper-zinc chelators reverse this process, dissolving the plaques. Moreover, copper potentiates the neurotoxicity of amyloid-beta, turning it into a pro-oxidant.[8]

In the laboratory, the copper-zinc chelator clioquinol dissolves amyloid-beta deposits in postmortem brain tissue from Alzheimer’s disease patients. A new study extends these results to mice genetically prone to overproduce amyloid-beta.[9] Clioquinol cut amyloid deposits in half over a nine week period with no adverse effects. The mice treated with clioquinol also exhibited significantly improved scores on a behavioral rating scale.

Curiously, clioquinol was sold as an oral antibiotic until it was withdrawn from the market in the early 1970s due to overdose-related neurological side effects now thought to be prevented by vitamin B12 supplementation. Clioquinol is now in FDA-mandated Phase II clinical trials, and will require several years of testing before it could reenter the pharmaceutical market as a treatment for Alzheimer’s disease.

For the foreseeable future, the significance of clioquinol research lies in its validation of copper-zinc chelation as an effective therapeutic mechanism for Alzheimer’s disease—a mechanism shared by an inexpensive natural agent that is currently available.

German scientists compared the ability of carnosine and anti-glycation drugs to block cross-linking of amyloid-beta, the process that generates senile plaques. One of the drugs, tenilsetam, has demonstrated clinical benefit in Alzheimer’s disease; the other drug was aminoguanidine. They incubated amyloid-beta with fructose, a sugar abundant in the brain that cross-links proteins up to ten times faster than glucose. All of the anti-glycation agents tested, including carnosine, prevented amyloid-beta from cross-linking, keeping it nearly 100% soluble.[10]

This laboratory finding suggests that formation of senile plaques can be prevented by inhibiting glycation, and we have already seen that copper-zinc chelation dramatically cuts amyloid-beta deposits. The relatively high levels of carnosine in the brain are not surprising when one considers that carnosine combines these two mechanisms, anti-glycation and copper-zinc chelation, with additional neuroprotective and antioxidant functions.

Rest here.

This article was printed in a "magazine" of a company that can supply drugs. So I keep that in mind when reading. But I think there's still some good info to be had here.

ces

as soon as we get to Texas:

Prevention of cognitive decline in Alzheimer's disease by ingested interferon alpha

In this phase I-II parallel design, randomized, double-blind clinical trial we will determine if 3,000 or 30,000 units ingested hrIFN-a prevents deterioration of cognitive functioning in patients with dementia of Alzheimer's type (AD) and whether ingested hrIFN-a treatment decreases acute phase reactants and pro-inflammatory cytokine IL-6 in mild to moderate AD. We predict that the novel anti-inflammatory agent ingested human recombinant interferon alpha (hrIFN-a) will modulate inflammation and inhibit the natural history of AD progression. If you are eligible, you will receive Aricept for 5 weeks (donezepil) and thereafter in addition to Aricept either placebo (inactive substance) or interferon alpha at 3,000 or 30,000 units every day for 12 months.
Condition Treatment or Intervention Phase
Memory Disorders
Alzheimer's Disease Drug: Aricept
Drug: IFN-alpha2A Phase II

Further Study Details:
Inflammatory mechanisms contribute to neurodegeneration in AD. Acute phase proteins such as the antichymotrypsin (a1ACT), pro-inflammatory cytokines IL-6 and IL-1, and activated microglial cells are all associated with neuritic plaques. a1ACT levels are elevated in AD, correlate with cognitive decline and serve as a biological marker of intervention. a1ACT is intimately associated with the 42-AA b peptide (Ab) in filamentous amyloid deposits and stimulates the polymerization of Ab into amyloid filaments. IL-6 is found in AD cortices prior to the onset of neuritic change, serum and stimulated PMNC IL-6 levels are higher in AD, and may induce b-amyloid protein deposition. Microglia, CNS resident inflammatory cells, produce IL-6 within the adult human brain, are IL-1a +, and are a prominent component of the neuritic plaque. Because the pathogenesis of AD appears in part immune mediated, we propose testing directly in humans whether ingested IFN-a can ameliorate AD. Because there is no good model for inflammation in animal models of AD, we will directly determine in humans 1) if 3,000 or 30,000 IU hrIFN-a inhibits the natural history rate of cognitive decline in mild to moderate AD using neuropsychological instruments as primary and secondary outcome measures that 2) correlates with inhibition of acute phase reactants and pro-inflammatory IL-6. If this novel anti-inflammatory agent inhibits the natural history rate of cognitive decline in AD in this pilot phase II trial, this would provide the preliminary data to submit a phase III clinical trial.

IFNs administered by the oral route show a systemic effect. Oral IFN-a caused neutropenia in mice. In contrast to their i.p. administration, oral IFN-a did not result in the presence of detectable levels of IFNs in the blood. Circulating specific antibody to IFN blocked the neutropenic effects of i.p. IFN, but did not block the neutropenic effects of the oral IFNs (2). Therefore, we examined the expression of antiviral MxA message, a type 1 IFN-specific induced signal, as a sensitive marker for type 1 IFN interaction with lymphoid cells in the gut-associated lymphoid tissue (GALT) using semi-quantitative RT-PCR on splenocytes from mice and PMNC from man after IFN-a ingestion. Both mice and man demonstrated inducible levels of Mx mRNA after ingesting IFN-a. Murine spleen T cells and CD8+ T cells also demonstrated upregulation of Mx mRNA. Therefore, ingested IFN-a acts via established pathways of type 1 IFN signalling (3). Elevated levels of activated T cells, mainly of the CD8+ (cytotoxic/suppressor) phenotype, are found in AD brains in contact with microglial cells (4). Interestingly, peripheral CD8+ T cells are depleted in AD patients (5). Lymphocytes bearing T helper and T cytotoxic/suppressor cell antigens are found in hippocampus and temporal cortex in AD (6,7). The data above suggest that lymphocytes are part of inflammation in AD, and potential immunomodulatory T and CD8+ T cells that contact ingested non-absorbed IFN in the GALT could migrate to the brain and decrease inflammation.

Read more here.

Found this through the Acurian Clinical Trial site I posted. I wish to hell is wasn't a double blind study, but it's really hard to find anything worth getting her into.

ces

Lemon and Lavender Could Help Dementia Patients
Thu Dec 5, 7:02 PM ET
(c) Reuters

LONDON (Reuters) - Alternative treatments such as aromatherapy could help elderly patients struggling with dementia, researchers said on Friday. Drugs and sedatives prescribed to control the symptoms of Alzheimer's and other forms of dementia often have uncomfortable side-effects.

Psychiatrists said some types of complementary medicine work and are well tolerated by elderly patients.

"Aromatherapy and bright light treatment seem to be safe and effective and may have an important role in managing behavioral problems in people with dementia," said Alistair Burns, a professor of psychiatry at the University of Manchester, England.

In an editorial in The British Medical Journal, he and his colleagues said three trials done in the past year have shown the benefit of aromatherapy, particularly the use of lemon balm and lavender oil, for dementia patients.

The oils contain compounds that are absorbed into the body and seem to improve some of the symptoms of the illness.

Studies have also shown that bright light therapy, which involves sitting in front of a light box, can also ease the restlessness and sleeping and behavioral problems which accompany dementia, according to the researchers.

"People with dementia are among the most vulnerable in our society. Symptoms often need to be treated expediently, and drugs, although moderately effective, can be hazardous," Burns added.

Dementia, including Alzheimer's disease, is a global problem affecting about 18 million people worldwide, according to the World Health Organization (news - web sites). The number of people with the disorder is expected to increase to 34 million in 25 years time.

Read the complete article here...

Can Light and Aromatherapy Treat Dementia? British researchers think so, but they have doubters
By Amanda Gardner
HealthScoutNews Reporter
(c) 2002 Health Scout.com

FRIDAY, Dec. 6 (HealthScoutNews) -- Aromatherapy and bright light therapy are safe, effective treatments and could play a role in managing behavioral problems in people suffering from dementia.

British researchers are making that argument in an editorial in tomorrow's British Medical Journal, but experts this side of the Atlantic are skeptical.

"I think the likelihood that this is going to revolutionize the care and treatment of Alzheimer's is very small," says William Thies, vice president for medical and scientific affairs at the Alzheimer's Association. But he adds, "It's good that people are talking about these kinds of issues. Enriching these kinds of environments is a good idea, especially if you can do it in a way that not only improves people's quality of life but is cost-effective."

Older people with dementia, such as that associated with Alzheimer's disease, often have psychiatric and behavioral problems, including agitation, delusions, wandering, hallucinations, and depression. These issues make caring for the person extremely difficult, often prompting caregivers to confine the patient in an institutional setting.

According to the journal authors, neuroleptic drugs (antipsychotics) and sedatives are often prescribed to deal with these symptoms, but they don't always work and come with side effects. And only two alternative therapies -- aromatherapy and bright light therapy -- appear to have any promise, the article says.

Aromatherapy is the use of essential oils (either extracts or essences) from flowers, herbs, and trees to treat mental and physical disorders. The editorial cites three trials in the last year that found it had significant benefits on agitation with almost complete compliance and virtually no side effects.

The two main agents in the studies were lemon balm and lavender oil, delivered either by smelling or absorbed via the skin. Although the researchers were not sure why the agents worked, they speculate that it was probably a direct chemical.

Dr. Alan Hirsch, neurological director of the Smell and Taste Treatment and Research Foundation in Chicago, has "mixed feelings" about the efficacy of such treatments.

"People with degenerative brain diseases have impaired olfactory ability," he says. "Also, the sense of smell drops down in older people. Half of people over age 65 and three-quarters of those over 80 have a reduced ability to smell."

The British Medical Journal article also found three controlled studies finding bright light therapy to be effective, this time on sleep disturbance. This type of therapy, which involves training a special light on the patient, is typically used for people with seasonal affective disorder (SAD).

The studies cited in the article all appear to have been conducted in Europe, and it's not clear how much research is ongoing in North America. "I hadn't heard of these particular studies," says Dr. Ellen Drexler, associate attending neurologist at Maimonides Medical Center in Brooklyn, N.Y. "I'm not that surprised that people are trying, but you're not going to find it too much in mainstream academic centers."

The studies cited also were not particularly large and, as Thies points out, many people with Alzheimer's and other dementias are often surviving in a fairly unstimulating environment. "It doesn't take much to show some improvement," he says.

That said, it's important to be researching such questions. "There are environments that are better, and I think the real problem is we don't know what all of those are and -- even more importantly -- we don't know the relative value of one intervention over another," Thies says.

Read the complete article here...

Vitamin Supplements Won't Prevent Dementia: Study
Mon Dec 2, 4:33 PM ET
By Juhie Bhatia

NEW YORK (Reuters Health) - Taking certain antioxidant vitamin supplements will not prevent dementia in old age, new study findings suggest.

While some previous reports have suggested that vitamin C and E may be protective against the development of dementia, the current study indicates that use of vitamin C and E supplements, taken separately or together, do not alter the risk of the disease. The findings are published in the November 13th issue of the Journal of the American Medical Association.

Dementia is caused by the progressive death of brain cells. Roughly 5% of the US population over the age of 65 suffers from some form of dementia, and the risk increases with age, Dr. Lenore Launer of the National Institute on Aging and senior investigator of the study told Reuters Health. Alzheimer's disease is the leading type of dementia in old age.

Researchers have suggested that formation of free radicals, which is blocked by antioxidant vitamins such as C and E, may be involved in the development of Alzheimer's disease and other dementias, Launer said.

The new study is based on data first collected in 1965 on Japanese-American men who were born in the early 1900s. Now named the Honolulu-Asia Aging Study (HAAS), it asked 2,369 of these men about their consumption of vitamin supplements in 1998 and through 1991-1993. Cases of dementia were then identified in two different assessments of the men, one in 1994 to 1996 and the other from 1997 through 1999.

The investigators found that compared with those taking no supplements, men using both vitamin C and E (either long- or short-term) were not at a reduced risk of developing dementia. There was also no association found between supplement use and dementia when the vitamins were taken separately.

"These results do not support the use of antioxidant vitamin supplements, particularly vitamin C and vitamin E, to reduce the risk for dementia," Launer said. "But other studies have shown mixed results and two recent studies showed that dietary intake of these vitamins did affect dementia but supplemental intake didn't."

Launer suggested that studies in other population groups at high risk of dementia be conducted to better determine if giving supplements for an extended length of time can actually prevent dementia.

SOURCE: The Journal of the American Medical Association 2002;288:2266-2268.

Read the complete article here...

Walking Problems May Predict Dementia: But researchers say preventive measures are possible
By Ed Edelson
HealthScoutNews Reporter
(c) 2002 HealthScout.com

WEDNESDAY, Nov. 27 (HealthScoutNews) -- Peculiar kinds of abnormal walking in the elderly can be warning signs of the mind-sapping condition called dementia, a study finds. Although this might sound very scary to an older person who is unsteady on his feet, it's actually good news, researchers say.

"The last thing I want to do is create a panic about walking slower," says Dr. Joe Verghese, assistant professor of neurology at Albert Einstein College of Medicine and lead author of a report on the finding, which appears in tomorrow's issue of the New England Journal of Medicine.

"Lots of people have difficulty walking when they get older, and 60 or 70 percent of the time it is caused by things like arthritis or back trouble," he adds."

The study didn't look at people with walking problems caused by arthritis. But other kinds of abnormal gait are warning signs of vascular dementia, which does not get the name recognition of Alzheimer's disease, the major cause of dementia in the aging, but does account for 30 percent of cases, Verghese says.

Gait problems included marked swaying, balance trouble, the inability to walk heel-to-toe, short steps, shuffling, not swinging the arms, and difficulty making turns.

"The surprise was how strong a predictor [abnormal gait] was and how it predicted into the future, at least 10 years into the future," Verghese says.

And that is good news because vascular dementia is potentially preventable. It results from diminished flow of blood to the brain, and measures can be taken to keep blood flow at a normal level -- "better control of blood pressure, better control of cholesterol," Verghese says.

The finding comes from the Einstein Aging Study, which has followed a large number of older people for more than two decades. This part of the study looked at 422 individuals between the ages of 75 and 85, whose gait was evaluated when they enrolled in the study. In a follow-up period averaging 6.6 years, 70 of the participants developed Alzheimer's disease and 47 developed vascular dementia. The people with neurological gait disorders had more than three times the risk of vascular dementia than those with normal gaits, although their risk of Alzheimer's disease was not affected.

It was known when the study began that an older person with dementia who had difficulty walking was more likely to have the vascular form, says Dr. Richard Lipton, the Lotti and Bernard Benson Faculty Scholar in Alzheimer's Disease at Einstein, who heads the aging study.

"What wasn't known previously, that this predicted the future development of vascular dementia, even a decade before diagnosis," he says.

Lipton sees the discovery as part of "a really fantastic shift in the field in the past two decades, from the view that dementia is not treatable. Two decades ago, the hope was finding the 10 percent of cases that might be treatable," he says.

"Today, we have three approved drugs for Alzheimer's disease, and some are also effective for vascular dementia. Already the condition has shifted from being rarely treatable to being almost always treatable," he adds.

The next transition, Lipton says, "is to make these conditions preventable. Treatment today does slow progression but is not fully curative."

Several preventive trials are under way, using a variety of drugs, ranging from estrogens to nonsteroidal anti-inflammatory drugs, Lipton says, "and the key to developing preventive intervention is to develop robust methods of identifying people at high risk."

The finding that an abnormal walking pattern can be a long-term warning of dementia can help doctors start preventive therapy early, he says.

Read the complete article here...

Age at Alzheimer's Diagnosis Affects Life Span
Mon Nov 18, 9:26 PM ET
By Alison McCook
(c) Reuters

NEW YORK (Reuters Health) - Just how Alzheimer's disease will affect a person's life span appears to depend greatly on the age at which the person is diagnosed, new study findings suggest.

Dr. Ron Brookmeyer of Johns Hopkins University in Baltimore, Maryland, and his colleagues discovered that people diagnosed with Alzheimer's disease in their 90s will likely live around 3 years longer, while those diagnosed 20 or 30 years earlier may have only 10 years of life left.

These findings indicate that the diagnosis has a much stronger impact on the life spans of younger patients than on those diagnosed near the end of their lives, Brookmeyer and his colleagues note.

It is important to predict how long people with Alzheimer's will live, the authors add. This information is especially helpful for the patients and people who care for them, Brookmeyer told Reuters Health, "so that healthcare providers and caregivers can plan accordingly and understand the likely course of the disease.

"The duration of survival is also important for determining the public health and economic effects of Alzheimer's disease in the population," Brookmeyer noted. "For example, we do not want to underestimate the public health burden of caring for persons with Alzheimer's which could happen if we underestimate duration of survival."

As the US population ages, researchers estimate that the nation's rate of Alzheimer's will quadruple over the next 50 years, when 1 in 45 people may be living with the disease.

Previous research has sought to determine the average life span for patients diagnosed with Alzheimer's, but has yielded conflicting results. A recent study estimated that the average patient will live slightly longer than 3 years after the diagnosis.

In the current study, reported in the November issue of Archives of Neurology, the authors followed a group of 921 dementia-free people over the age of 55 who were enrolled in a study that began in 1985. The participants checked in with investigators approximately every 2 years through 1999.

Over the course of the study, the researchers diagnosed 108 people with Alzheimer's. People who were diagnosed at age 65 tended to survive for up to 9 years longer, while those who developed Alzheimer's at 90 lived with the disease for roughly 3 additional years.

As a result, Brookmeyer's team calculates that Alzheimer's reduced the average years remaining in the life of a 65-year-old by 67%, but cut the years left for a 90-year-old by only 39%.

In an interview with Reuters Health, Brookmeyer stressed that these figures represent an average, and each patient with Alzheimer's can live for many years longer than estimated. "These are statistical averages," he said, "and any particular person with Alzheimer's disease could live somewhat longer or less."

SOURCE: Archives of Neurology 2002;59:1764-1767.

Once Again, Wine Boasts Brain-Boosting Benefits
Study says it appears to protect against dementia later in life
By Randy Dotinga
HealthScoutNews Reporter
(c) MDChoice.com

MONDAY, Nov. 11 (HealthScoutNews) -- In another sign that chardonnay and Bordeaux may be as healthful as fruits and vegetables, a new study provides more evidence that wine can protect the brain from the ravages of Alzheimer's disease.

However, experts still aren't advising people to run out to the liquor store unless they already had planned a trip.

"It is still premature to talk about wine as a 'health food' product," says study co-author Dr. Thomas Truelsen, a researcher at the Institute of Preventive Medicine at Kommunehospitalet in Copenhagen, Denmark.

Even if wine does protect the brain, the Danish study suggests beer does the exact opposite. The study findings appear in tomorrow's issue of Neurology.

Wine, of course, is gaining a reputation as much more than just a requisite beverage for dinner parties. Researchers in recent years have linked it to lower risks of heart disease, and wine drinkers seem to have healthier habits than teetotalers.

The Danish researchers examined reports from the 1970s on the alcohol-drinking habits of 1,709 people. Then the researchers followed up by looking into how many of the study subjects developed dementia, a major symptom of Alzheimer's disease, in the 1990s.

Dementia refers to the loss of memory, concentration and other brain functions due to disease. Eighty-three of the participants developed the symptom.

People who drank wine weekly or monthly were more than two times less likely to develop dementia than others in the study. Drinking wine every day appeared to have no effect on the risk of dementia, and drinking beer monthly actually increased the risk.

Other studies have shown a link between wine drinking and lower risk of dementia, Truelsen says. The researchers behind the new study think that plant-derived substances in wine known as flavonoids may provide protection to the brain. Flavonoids are more common in red wine than white wine, but they are also found in other foods, raising questions about whether they're really responsible for wine's beneficial effects.

Truelsen says the researchers don't know why beer consumption was linked to a higher risk of dementia in the people studied. "It may be that intake of beer is associated with a poorer diet or trauma, or that their drinking patterns are different," he says.

He acknowledges the study didn't account for the diets of the participants, which could affect their overall health. For that reason and others, the findings of the new study aren't firm enough to allow a recommendation about wine consumption, he says.

Also, he adds, "There may be many good reasons for stopping drinking --- health, family, pregnancy, economy, work, etcetera."

Bill Thies, vice president for medical and scientific affairs for the Alzheimer's Association, agrees that a blanket endorsement of wine consumption for all would be a bad idea.

"For example, there are people who are genetically prone to alcoholism who avoid alcohol," he says. "Recommending that everyone drink red wine for the health of their brain may expose such people to alcohol, with severe health consequences."

Read the complete article here...

Trials and Tribulations: Does ADAPT Have to Adapt?
by Gabrielle Strobel
Alzheimer Research Forum

25 September 2002. When planning prospective clinical trials, one of trickiest challenges facing researchers lies in picking the right targets and drugs. In planning a prevention trial, for example, they must integrate strict safety requirements with data from existing research while also minimizing the possibility that future studies conducted during the trial’s multi-year duration will not call into question the original design.

This perennial problem was underscored recently, when the Washington-based consumer advocacy group Public Citizen sent an open letter to the Department of Health and Human Services, recommending that an ongoing 7-year AD prevention trial of two non-steroidal anti-inflammatory drugs be suspended. The letter charged that the drugs tested in this multi-center trial, naproxen and celecoxib, had insufficient scientific support and that the informed consent document used to enroll trial participants was inadequate. (See at http://www.citizen.org/publications/release.cfm?ID=7195.)

The Alzheimer Research Forum interviewed the study’s principal investigator, John Breitner of University of Washington, Seattle, about the issues underlying this letter. The Breitner Q&A and comments from 11 other scientists in the field appear below.—Gabrielle Strobel.

Read the complete article here...

PET Reduces Alzheimer Misdiagnosis
by Tom Fagan
Alzheimer Research Forum

8 October 2002. Enormous strides have been made in the development of whole brain imaging techniques as tools for diagnosing and monitoring neurodegenerative diseases such as Alzheimer's (see related news item from the imaging symposium at the Stockholm meeting). Among these different methodologies, positron emission tomography (PET) is likely to be among the first to deliver a standard diagnostic tool that can be used in the clinic, as it has already proven itself capable of diagnosing AD with a high degree of accuracy (see related news item). One question that remains, however, is whether PET can improve on the battery of diagnostic tests that are already in use.

A report in this month's Molecular Imaging and Biology suggests that it can. Daniel Silverman and colleagues at the University of California, Los Angeles, tested the ability of 2-deoxy-2-[18F]fluoro-D-glucose PET, which monitors neuronal fitness by measuring glucose metabolism, to improve diagnosis in the clinic.

The authors separated patients into two groups. Both received standard tests for Alzheimer's disease as recommended by the American Academy of Neurology, but only one group was given the additional benefit of the PET scan. The imaging analysis was found to decrease the number of false negatives by five percent and the number of false positives by more than 10 percent.

The benefit of PET, according to the authors, is immense for those who have some degree of cognitive impairment but are misdiagnosed. The number of months spent on unnecessary drug therapy for those who appear to have the disease but later turn out to be AD-free could be halved. So too could the time spent on eventual nursing home care for those who are in the beginning stages of the disease but go without precious early intervention.—Tom Fagan

Reference:
Silverman DHS, Cummings JL, Small GW, Gambhir SS, Chen W, Czernin J, Phelps ME. Added clinical benefit of incorporating 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography into the clinical evaluation of patients with cognitive impairment. Mol. Imaging Biol. 2002 October. 4:1-11.

Read the complete article here...