ALZHEIMER

UPDATE

DR. JAMAL AL-KHATIB

 Alzheimer Update
Diagnosis:
1-
Diagnosis Scandal Threatens Alzheimer's Diagnostic Test
January 18, 1999

Last April, an expert panel of the National Institutes of Health declared that
the Alzheimer's diagnostic test developed by Athena Neurosciences, Inc., of
South San Francisco, California, was significantly better than rival tests. The
announcement spurred sales of the test, which rose 28 percent during 1998.
Athena's test analyzes blood for the various forms of the gene for
apolipoprotein E, some of which have been linked to an increased risk of
Alzheimer's.

But last month, the Wall St. Journal reported that five of the expert panel's
eight members had financial ties to Athena, possibly tainting their
conclusion about the company's Alzheimer's test. In addition, Athena gave a
$100,000 grant to the nonprofit Alzheimer's Association, the nation's leading
Alzheimer's organization to organize the panel for the NIH. Since the cozy
relationship between the experts and Athena was divulged, the Alzheimer's
Association has said that it regrets having used the funds to support the
panel's work.

The panelists insist that the conclusion of their report is scientifically solid,
that Athena's test is better than the competition's. Their endorsement was not
unqualified. Athena's test does not provide a definitive diagnosis of
Alzheimer's. That can still not be determined until autopsy.

But Nymox Corporation, which makes a competing test, has cried foul,
saying that the panel had a conflict of interest and that the Alzheimer's
Association and the NIH should have taken action, but did not.

Experts familiar with the workings of government expert panels say that it's
not unusual for some experts to have some ties to companies whose products
they evaluate, but they concede that five of eight raises questions about
credibility.

1
Most physicians have not jumped to perform tests for Alzheimer's--Athena's,
Nymox's, or any other. The current flap will probably reinforce physician
reluctance to use any of these tests.

Source: Wall St. Journal

2-
Brain Scans Detect Earliest Signs of Alzheimer's Disease
February 1, 1999

In an advance that may provide a way to definitively diagnose early

Alzheimer's--possibly even before any memory loss occurs--a key memory
center in the brain shrinks substantially in those with very mild Alzheimer's,
a new study shows.

Researchers at New York University School of Medicine used MRI scans to

measure anatomical changes in an important memory center, the entorhinal
cortex. They discovered that this area shrinks substantially in those with very
mild Alzheimer's. MRI scans are a powerful imaging tool that can peer
inside the head to create an anatomical snapshot of the brain.

"We have found a way to measure what may be the earliest changes in the
memory-processing areas of the brain," says Dr. Mony de Leon, professor of
psychiatry at NYU School of Medicine. This technique can be performed
rapidly and potentially may be used to monitor the effect of therapies on the
course of Alzheimer's disease, says Dr. de Leon, who is Director of the NYU
School of Medicine Neuroimaging Research Laboratory.

Currently, physicians diagnose Alzheimer's by evaluating a person's

performance on tests of memory and learning, taking a thorough medical and
family history, and performing a physical examination. But the disease is
difficult to diagnose in its initial stages because there are no definitive
laboratory tests.

The new study extends previous findings by Dr. de Leon and other
researchers that the hippocampus, another region of the brain associated with
memory and learning, diminishes in size as Alzheimer's progresses.

2
The progressive damage and loss of neurons is one of the hallmarks of
Alzheimer's disease. Previous studies by a German research team indicated
that the damage begins in the entorhinal cortex as early as age 30 and
spreads to the hippocampus. However, without MRI, this deterioration has
been impossible to monitor.

"The entorhinal cortex is the gateway to the hippocampus and is central to

all memory functions in the brain," explains Dr. de Leon. "It is a memory
distribution and processing center and if its gate is broken, then new
memories cannot be made and old memories cannot be retrieved."

In the new study, Dr. de Leon and co-workers developed a new method of
measuring the size of the entorhinal cortex based on structural landmarks
visible on MRI.

The researchers used autopsied brain tissue from Alzheimer's sufferers and
from control subjects who died of conditions unrelated to the brain to
establish that the landmarks could be used to define the boundaries of the
entorhinal cortex, providing a valid tool for measuring its surface area. The
landmark-measurement technique revealed that the entorhinal cortex was
reduced by 45 percent among Alzheimer's patients.

Next, the researchers used the landmark technique to distinguish those with
very mild Alzheimer's from healthy volunteers. They found that the
entorhinal cortex was 27 percent smaller in patients with very mild
Alzheimer's. Moreover, the damage to the entorhinal cortex was greater than
to the hippocampus and it proved a more reliable disease marker.

Source: NYU Medical Center, Lancet

3-
Is It? Diagnosis Alzheimer's Diagnosis: Why All the Delays?
April 19, 1999

It takes an average of 30 months from the time family members notice

the initial symptoms of dementia for the person to be diagnosed with
Alzheimer's, according to a new study by Linda Boise, Ph.D., M.P.H.,
and colleagues at the Oregon Health Sciences University in Portland.

3
 The researchers conducted in-depth interviews with 244 primary
caregivers and other close family members in order to understand why
the diagnostic process takes so long.

The single biggest reason, cited by 72 percent of caregivers, was that

they knew very little about Alzheimer's disease, and for a long time
simply did not imagine that the person's changing behavior and
deteriorating cognitive abilities were manifestations of an illness. Half
of caregivers said they thought the changes were a normal part of
aging.

Here are selected other reasons for delay of diagnosis:

• I didn't know what kind of doctor to see (44%).

• I felt overwhelmed by the increasing burden of caregiving
(42%).
• I didn't know how to explain the problems to my doctor (38%).
• My doctor did not take my concerns seriously (29%).
• I didn't have a chance to talk to the doctor in private (27%).
• The doctor said my loved one's problems were a normal part of
aging (25%).
• I did not want to know that the illness was Alzheimer's
(20%).

The caregivers also said that during the period before the diagnosis,
they became increasingly anxious as the person deteriorated. When
the diagnosis was finally made, most caregivers said they felt relieved.

Source: American J. of Alzheimer's. Disease

Urine may be used to diagnose Alzheimer's disease

4
NEW YORK, Aug 02 (Reuters Health) -- A new urine test that can assist in
the diagnosis of Alzheimer's disease has been developed, according to
researchers reporting last week at the 51st annual meeting of the American
Association for Clinical Chemistry in New Orleans.
The AD7C neural thread protein urine test measures urine concentrations of
the protein, which is elevated in patients with Alzheimer's disease. In their
study of more than 200 patients with Alzheimer's, Dr. Michael Munzar and
colleagues at Nymox Pharmaceutical Corp. of Montreal, Canada, found that
the average level of neural thread protein was 2.3 ng/ml compared with
levels of less than 1.5 ng/ml for patients with other types of neurological
diseases, and 0.83 ng/ml for healthy "control" subjects.
Munzar, medical director of the company, presented his group's findings at
the meeting. In an interview with Reuters Health, he said that the test has
been accurately picking up Alzheimer's in about 80% of cases and has been
correctly negative about 90% of the time. The test has been made available
commercially, he noted.
"Samples are sent to our reference laboratory in Kensington, Maryland. It's
new, but physicians are using it."
Munzar added that "it's not a predictive test... it's a state marker, a
biochemical marker." He said that preliminary evidence indicates a
correlation between level of elevation of neural thread protein and severity
of Alzheimer's disease, "but we're very cautious about that. People are
beginning to do baseline tests in (high-risk subjects) with family histories of
Alzheimer's disease.... In patients with subtle, marginal symptoms, you may
get elevations (of AD7C)."
Nymox is in the process of developing a 7C assay, which is a quicker, more
advanced test compared with AD7C. "It can be turned into a kit for direct
use by physicians, without having to go through our reference laboratory,"
Munzar explained.

Rule Out These Drugs Before Diagnosing Alzheimer's

August 18, 1998

5
Some physicians are not sufficiently informed about the large number of
medications that can cause drug-induced dementia. They may diagnose
Alzhiemer's when a drug reaction is actually the cause, says Bruce Robinson,
M.D., a professor and chief of the division of geriatric medicine and the
University of South Florida in Tampa.

The list includes such drugs as aspirin and Motrin, which in large doses over
long periods of time, for example, in treatment of arthritis, can impair
cognition.

Other drugs that may cause enoughtcognitive impairment to raise suspicion

of Alzheimer's include:

Nonsteroidal Anti-Inflammatory Drugs (NSAID's):

Advil, Nuprin, ibuprofen, Naprosyn, naproxen, Indocin, indomethicin,
Clinoril, sulindac.

Antihistamines and Decongestants:

Found in cold and allergy forumlas, for example, Sudafed, Chlor-Trimeton
and Tavist products.

Benzodiazepines:
Valium, Xanax, Librium, Serax, Oxazepam, Ativan, Lorazepam,
Alprazolam, Diazepam,Tranxene.

Antidepressants:
Prozac, Paxil, Zoloft, Elavil, Tofranil, Norpramin.

Anticonvulsants:
Dilantin, Depakene, Depakote, valproic acid, Tegretol, Depitol,
phenobarbitol.

High blood pressure medication:

Atenolol, Tenormin, Brevibloc, Kerlone, Catrol, Zebeta, Prindolol, Visken,
Lopressor, Toprol, Blocadren, Timolol, Betapace, Corgard, Nadolol,
Acebutolol, Inderal, propranolol, Calan, Isoptin, verapamil.

Ulcer/Stomach medication:
Tagamet, cimetidine, Zantac, ranitidine

6
Antibiotics:
Keflex, Keflin, Flagyl.

Antiparkinson's drugs:
Larodopa, Dopar, Parlodel, Permax

Heart failure medication:

Digoxin

Corticosteroids:
Prednisone

Narcotics:
Codeine, Percodan, Percocet

Source: Geratrics (1997) 52:12:30

Pathology

7
 1-
Brain Cell Snapshots Provide Clues to Alzheimer's Disease Process
October 26, 1998

A new imaging technology allows scientists to take genetic "snapshots" of

brain cells affected by Alzheimer's. The new technology, developed at the
University of Rochester, enables researchers to assess the activity of 20
genes simultaneously. The genes under investigation are believed to play a
role in the Alzheimer's disease process.

In Alzheimer's, brain cells die, but not all cells in any given area are affected.
Healthy cells and Alzheimer's-affected cells are remarkably interspersed.
The new technology allows scientists to analyze their activity, which, they
hope, will shed new light on how the disease progresses, and how healthy
cells resist it.

Of the 20 genes tested, five showed significant differences between healthy

cells and Alzheimer's-affected cells. The five genes all play a role in
regulating cell division and telling the cell when to die. Many of these genes
also play a role in cancer, raising the possibility that Alzheimer's might be a
special, unique form of brain cancer, according to Paul Coleman, principle
investigator.

Now Coleman's team is comparing the activity of up to 100 genes in healthy

and diseased brain cells using the new technology that combines laser
microdissection with genetic analysis techniques. His team hopes that by
studying thousands of genes, they will eventually be able to create a genetic
map showing which genes are involved in Alzheimer's, and in what
sequence.

Source: American Journal of Alzheimer's Disease

Scientists Uncover Possible Trigger for Alzheimer's Disease
June 23, 1998

Researchers may have uncovered one of the first links in the long chain of
biological events that cause Alzheimer's disease.

8
Dr. Mary P. Lambert, of Northwestern University, and colleagues studied
how toxic proteins known as amyloid beta-derived diffusible ligands, or
ADDLs, interact with nerve cells in laboratory animals.

ADDLs were discovered only recently and have been found in the brains of
people with Alzheimer's disease in the form of long fibers. Scientists had
thought that these weed-like fibers somehow choked off the growth of nerve
cells, causing them to die away. When this happened, many scientists
believed, symptoms of dementia would begin to occur.

But Lambert and her colleagues discovered that ADDLs may gum up the
nerve cells' chemical machinery much earlier, long before they begin to die
off, and in the process prevent the cells from carrying out activities needed
for learning and memory.

The finding may give scientists a way to intervene in the Alzheimer's disease
process before it damages the nerve cells, said researcher Dr. Grant A. Krafft
of Evanston Northwestern Healthcare. "The implication of this work is that
if Alzheimer's disease symptoms are caught at early stages, they potentially
could be reversed," said Krafft.

Source: Proceedings of the National Academy of Sciences (1998) 95:6448-

6453
Who Becomes Agitated? Who Becomes Verbally Abusive?
November 3, 1998

When institutionalized, demented elderly often become physically agitated

and verbally abusive/aggressive. But it's been hard to predict who will
develop which problem. Researchers from the University of Pennsylvania,
the Medical College of Georgia, and Wilkes University in Wilkes-Barre, PA
believe they have solved this puzzle.

Over 12 months, the researchers studied 586 nursing home residents with
either agitated behavior (AB) or verbally aggressive behavior (VAB), along
with 184 controls who displayed neither syndrome.

Agitation turned out to be closely related to cognitive impairment. Compared

9
with cognitively normal elders, those with cognitive impairment were more
likely to display AB. In those with severe cognitive decline, AB was four
times more likely.

On the other hand, verbal aggression was more related to use of drugs aimed
at controlling unruly behavior. As drug use increased, residents were less
able to act out physically, so they became more likely to resort to VAB.

The best predictor of AB and VAB was previous similar behavior. Some
people, it seems, gravitate toward verbal aggression while others tend toward
physical outbursts.

Source: American Journal of Alzheimer's Disease

Age-Related Brain Cell Loss Reversed In Animals
By Pam Harrison

NEW YORK, Sep 20 (Reuters Health) -- For the first time, scientists have shown that brain cell changes
associated with aging and memory loss are potentially reversible in animals.

The findings may lead to therapies that fight age-related loss of brain cells.

Drs. Heather A. Cameron and Ronald D.G. McKay from the National Institutes of Health, Bethesda,
Maryland, surgically removed the adrenal glands in a group of aged rats to see if reducing stress hormones
normally produced by these glands might restore nerve cell growth in the hippocampus, a part of the brain
responsible for certain types of learning and memory. In a report of their findings published in the October
issue of Nature Neuroscience, the researchers explain that it is believed that high levels of corticosteroids
or adrenal stress hormones either cause or accelerate damage to this particular area of the brain, resulting in
decreased cell production and memory loss associated with normal aging.

The investigators found that by surgically reducing stress hormone production, the growth of new nerve
cells was restored in the brains of aged rats to the same extent as it occurs in younger rats.

These findings indicate that the ability of the brain to generate new nerve cells continues into old age, but
that it is slowed down by high levels of stress hormones, they note. In an interview with ReuHealth,
McKay noted that his team needs to generate more data to support the idea that high levels of
corticosteroids are an important regulator of memory loss in humans, as they are in rats.

"If it holds true, then we need to exploit our pharmacological skills to specifically target this particular
aspect of corticosteroid action and leave the other, beneficial actions of stress hormones intact," he said.
This is not as difficult as it might seem, he added. Right now, a class of drugs already exists that can turn
on estrogen in specific parts of the body but not, desirably, in the breast or the uterus.

McKay also noted that steroid receptors, proteins on cells that interact with the hormones, also "come in
different flavors, and it is quite possible to target receptors in the hippocampus by making a drug that binds
only to receptors in this part of the brain but not to others." Once inhibited by such a drug, corticosteroid
levels in the brain could be controlled, and nerve cell growth may thus continue into old age, thereby
preventing memory loss, McKay suggested.

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SOURCE: Nature Neuroscience 1999;2:894-897.

Head Trauma Linked To Degenerative Brain Changes

NEW YORK, Aug 31 (Reuters Health) -- Trauma to the head may trigger a cascade of biochemical events
in the brain, in time resulting in neurodegenerative changes similar to those found in patients with
Alzheimer's disease, report researchers at the University of Pennsylvania in Philadelphia.

The findings back previous studies that suggested brain trauma increases the risk of Alzheimer's disease, a
leading cause of dementia, later in life.

In a statement, the researchers say that they hope their study will lead to a renewed commitment to educate
the public about behaviors that reduce the risk of head injury, such as wearing seatbelts while traveling in
an automobile and helmets while riding bicycles or motorcycles.

Dr. Douglas H. Smith, who led the research effort, told Reuters Health that these findings support "several
epidemiologic reports (that have suggested) a link between a single episode of brain trauma and the
development of Alzheimer's disease later in life."

Smith's team induced brain injury in anesthetized pigs via very rapid acceleration/deceleration of the
animals' heads without direct impact, similar to what humans often experience in an automobile accident.
They describe their experiments in the September issue of the Journal of Neuropathology and Experimental
Neurology.

"Brain trauma is the only environmental risk factor for Alzheimer's disease, so there is something about
brain trauma that might initiate these insidious neurodegenerative cascades," Smith said in the interview
with Reuters Health.

Analysis of brain tissue from the animals revealed diffuse axonal pathology, the scientists report. "The
most remarkable and consistent finding," they write in the paper, "was extensive (amyloid beta) and tau
accumulation in damaged (brain cells) following trauma." Amyloid beta protein is a characteristic finding
in the brains of patients with Alzheimer's disease. In the study animals, these changes were evident as early
as 3 to 10 days post-injury.

Smith said that some of the brain-injured animals, his group also observed plaque formation, another
typical finding in Alzheimer's disease.

The team conclude that microscopic injury to the brain caused by trauma can be linked to the development
of Alzheimer's disease many years after the injury.

The finding may also lead to new drugs aimed at preventing the process. "This study adds to the body of
knowledge that might aid us in the development of an anti-plaque-making compound," Smith said in a
statement.

SOURCE: Journal of Neuropathology and Experimental Neurology 1999;58:982-992.

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 Alzheimer’s disease
Steve Simpson and Alistair Burns
Current Opinion in Psychiattry 1996. 9:89-92

Introduction
This review focuses on clinical research into Alzheimer’s disease, the
commonest form of degenerative dementia. Although in recent years there
have been developments in the treatment of the cognitive impairment [1,2],
this year more progress has been made in the genetics of Alzheimer’s
disease. In particular, a gene (S182) responsible for an estimated three-
quarters of presenile familial Alzheimer’s disease has been located on
chromosome 14 (14q24.3). Other studies, including Alzheimer’s disease
with depression and extrapyramidal signs in Alzheimer’s disease, are
discussed.

Genetics
Early onset Alzheimer’s disease is generally considered to be geneticallly
determined. The evidence that late onset Alzheimer’s disease is familial is
less strong and when no family history exists patients are diagnosed as
having sporadic Alzheimer’s disease. At least three different genes have
been identified that confer susceptibility; previous molecular genetic studies
have implicated chromosomes 19, 21 and 14.
(1) The e4 (112 Cys-Arg) allele of apolipoprotein E4 is
associated with as much as 50% of all cases of Alzheimer’s
disease. Apolipoprotein E4 is a plasma protein involved in the
metabolism of cholesterol and triglycerides and its gene is linked
to chromosome 19 [3].
(2) On chromosome 21, several missense mutations in the
beta-amyloid precursor precursor protein represent a proportion
of both familial Alzheimer’s disease and sporadic Alzheimer’s
disease [4].
(3) Genetic linkage studies have mapped a third locus
associated with susceptibility to an aggressive form of
Alzheimer’s disease, to chromosome 14; the elucidation of the
gene is anticipated [5].
This year a missense mutation was reported [6**]. In a genetic mapping
study of 21 pedigrees, segregating Alzheimer’s disease as a putative
autosomal dominant trait, one of the transcripts on the Alzheimer’s disease

12
gene (S182) corresponded to a novel gene, the product of which is predicted
to contain multiple transmembrane domains and to resemble an integral
membrane protein. Strong evidence now exists that mutations in the S182
gene are the cause of early onset familial Alzheimer’s disease in some
pedigrees. The S182 protein is most homologous to another protein called
SPE-4, found in the sperm of the round worm. SPE-4 is a membranous
protein involved in intracellular transport or interactions with fibrillar
proteins [7], which are relevant in the cytopathological mechanisms in
Alzheimer’s disease [3,8]. S182 is envisaged to be involved in aberrant
transport and processing of beta-amyloid precursor protein at a cytoskeletal
level or to interact with cytoskeletal proteins such as microtubule Tau.
Abnormalities in the intracellular, and ultimately, extracellular disposition of
both these proteins are an integral part of the neuropathology of Alzheimer’s
disease. How S182 interacts with beta-amyloid precursor protein or
apolipoprotein in the pathogenesis of Alzheimer’s disease remains to be
found; further research will determine its clinicopathological significance.

The clinicopathological correlates of aplipoprotein e4 were studied by

Zubenko et al. [9], who found no association between the allele and
cerebrovascular disease in Alzheimer’s disease. The group suggested that the
apolipoprotein e4 allele may contribute more to the formation (or decreased
resorption) of senile plaques, the defining lesions in Alzheimer’s disease,
than to the formation of neurofibrillary tangles. The authors also suggested
that amyloid angiopathy may be a more central feature of a form of familial
Alzheimer’s disease associated with the apolipoprotein e4 allele.

The predicative effect of possessing the allele has received attention. In a

Dutch male population, it was well charted in a 3-year prospective study
[10**]. A random sample of normal elderly men (n = 538, aged 65-84 years)
was examined. The rate of cognitive decline was greatest for men who were
homozygous for e4 and intermediate for heterozygous patients. Using odds
ratio statistic to calculate attributable risk, 22% of the risk of developing
impaired cognitive function was attributed to the e4 allele, predicting that
elderly men with this allele are at twice the risk of developing cognitive
impairment. In another prospective study, apolipoprotein E4 status was the
strongest predictors of the development of Alzheimer’s disease [11].

13
Clinical studies
Noncognitive features
Noncognitive features of dementia (that is, psychiartic symptoms and
behavioural disturbances) continue to be the focus of research with
increasing recognition that neuropsychological impairment is only one part
of the clinical spectrum and even the early manifestations of Alzheimer’s
disease are often noncognitive [12].

One of the most common psychiatric associations of Alzheimer’s disease is

depression and the estimated prevalence varies from 0 to 86% [13]. The
variation presumably reflects different methods of measurement, different
sample selection and, perhaps, stage of illness. Establishing depression in
dementia is problematic [14]; the measures used need to be designed for
specialist use in dementia, such as the Cornell Scale for Depression in
Dementia (CSDD). Vida et al. [15] found that a cutoff of seven points on the
CSDD had a sensitivity of 0.9 and a specificity of 0.75 for depressive illness
(using Research Diagnostic Criteria for depressive illness as the gold
standard). The under-reporting of depressin will clearly affect prevalence
rates [16] and carer-based assessments, such as those used in the CSDD, may
be more sensitive. The finding that care givers can reliably act as surrogate
reporters for depression in Alzheimer’s disease [17**] may be of practical
help in the detection of depression in dementia. In this study [17**] of 76
patients with Alzheimer’s disease, the carers completed measures of
depression on behalf of the patients. The surrogate assessments included a
modified Beck Depression Inventory, the Geriatric Depression Scale and the
Centre for Epidemiological Studies Depression Scale. The interview
depression measures included the Hamilton Depression Rating Scale and the
CSDD. The CSDD was found to be the most sensitive measure of depression
and the Hamilton Depression Rating Scale the least. The authors concluded
that care givers were able to act reliably as surrogate reporters for depression
in Alzheimer’s disease.

The wide range in quoted prevalence of depression in Alzheimer’s disease

was discussed by Weiner et al. [18*] who examined two cohorts of patients
with Alzheimer’s disease. The authors found a low prevalence and incidence
(1.5% prevalence and no incident patients in one cohort and a 1.3%
incidence over 2 years in the other). This suggests that established
Alzheimer’s disease did not predispose to depressive illness, at least as
defined in DSM-III-R, and major depression may herals the onset of

14
dementia. Migliorelli et al. [19*] differentiated dysthymia from major
depression and found 28% prevalence for dysthymia for major depression.
(Women were over-represented in both groups). Dysthymia was associated
with the early stages of dementia and with low scores of anosagnosia
compared with the group with major depression. In contrast, patients with
major depression had an early onset of depression often before the diagnosis
of dementia and its prevalence was similar across progressing stages of the
illness. Major depression was not associated with anosagnosia and the
authors postulated that, compared with dysthymia, major depression was less
related to emotional factors. In another study of depression in Alzheimer’s
disease, albeit with small numbers [20*], no difference was found in
depression between two groups with and without anosagnosia.

Neuropsychology
The differentiation of depression and dementia is a common clinical problem
and Lacher and Engel [21], in a meta-analysis of 16 publications, found that
a delayed retrieval memory task with distraction gave the best
discrimination. In a study of major depression [22], with an average of 59
years and severity of 30 on the Hamilton Depression Rating Scale, the
authors were unable to recommend clinical neuropsychology tests that could
differentiate depression from early Alzheimer’s disease, despite the fact that
the two groups posed no particular diagnostic difficulty. The differentiation
of depression from early Alzheimer’s disease by neuropsychology is
probably more difficult than previous research suggests.

Extrapyramidal signs
These are a recognized feature of Alzheimer’s disease [23]. Investigators
have estimated their prevalence at 56% they were identified as parkinsonism
in 23% [24**]. Alzheimer’s disease with extrapyramidal signs has
distinguishing clinical features characterized by a greater rate of cognitive
decline [25], depression [24**] and deficits in executive function [24**, 26].
Patients extrapyramidal signs deteriorate by an additional 1.3 points on the
Mini-Mental State Examination every 6 months [25]. Higher education,
younger age and agitation are also risk factors for more rapid decline in
Alzheimer’s disease [27]. Merello et al. [24**] found depression to be
associated with extrapyramidal signs, in terms of both diagnosed depression
(DSM-III-R) and severity, using the Hamilton Depression Rating Scale. In
the depressed group, the accompanying neuropsychological impairments

15
were predominantly frontal with deficits measured on tests such as verbal
fluency, Wisconsin card sort test and abstraction.

Neuroimaging
Magnetic resonance imaging has focused on temporal lobe structures in the
radiological diagnosis of Alzheimer’s disease. The appearance of medial-
temporal lobe atrophy has been used to differentiate Alzheimer’s disease
reliably from depressive illness [28*]. Forty-three patients with Alzheimer’s
disease were compared with 32 patients with depression using a visual rating
of hippocampal atrophy; 89% of patients were correctly diagnosed.
Furthermore, the comparison of Alzheimer’s disease with individuals
suffering from the dementia syndrome of depression resulted in correct
discrimination in 84% of patients. Authors of T1 study [29] of temporal lobe
structures concluded that hippocampal and parahippocampal atrophy were
more useful than necortical atrophy in the earliest detection of Alzheimer’s
disease. The radiological diagnosis of clinical Alzheimer’s disease based on
temporal lobe measures appears to be reliable and this has been substantiated
by neuropathological studies [30].

Bennett et al. [[31] reported on a number of studies looking at white matter

changes found by magnetic resonance imaging in Alzheimer’s disease and
Binswanger’s disease. The authors concluded that Binswanger’s disease,
compared with Alzheimer’s disease. The radiological diagnosis of clinical
Alzheimer’s disease based on temporal lobe measures appears to be reliable
and this has been substantiated by neuropathological studies [30].

Bennett et al. [31] reported on a number of studies looking at white matter

changes found by magnetic resonance imaging in Alzheimer’s disease and
Binswanger’s disease, compared with Alzheimer’s disease, was associated
with episodic memory defects, more depressive features, gait disturbance
and more variable cognitive decline. In Alzheimer’s disease, some of the
white matter lesions were associated with incontinence and gait disturbance
but did not contribute to the severity of dementia.

In a single photon emission computerized tomography study of delusions in

Alzheimer’s disease, decreased regional cerebral blood flow bilaterally in
the temporal lobes characterized the psychotic group but they had no
differentiating neuropsychological profile [32]. Anosagnosia in Alzheimer’s
disease has been studied because of its possible relation to depression.

16
However, in one study [20*], although anosagnosia was not associated with
depression, it did correlate with blood flow deficits in the frontal inferior and
superior (dorsal) areas in the right hemisphere. This region of interest was
not found to be associated with any particular neuropsychological profile.

Conclusion
Progress in the field of Alzheimer’s disease has been rapid over the past 12
months, the most dramatic findings being genetic. Further research into the
S182 gene will follow the directions taken after the discovery of the first
beta-amyloid precursor protein mutation on chromosome 21. More useful
treatment may follow from a better understanding of the influence of
susceptibility genes on the pathogenesis of Alzheimer’s disease.
Noncognitive complications continue to be of prime interest and a number of
significant contributions have been made to understanding depression.
Extrapyramidal signs appear to be an important accompaniment of
Alzheimer’s disease in terms of predictors of cognitive decline. Currently,
the benefits of cognitive enhancing drugs are modest but further trials are
being evaluated.

Treatment
Until recently, nothing seemed to slow the inexorable mental
decline of people with Alzheimer's disease.

Until recently, nothing seemed to slow the inexorable mental decline

of people with Alzheimer's disease. But recently, as researchers have
learned more about the development of Alzheimer's, several
promising treatments have been identified, two have been approved,
and many more are in development.

Treatment of Alzheimer's disease is still in its infancy, and experts are

quick to concede that they have a long way to go. But today, for the
first time, researchers have become cautiously optimistic that in the
not-too-distant future, new treatments should be able to delay the
onset Alzheimer's disease, and slow the mental deterioration it causes.
Many predict that within the next decade or so, it will become a
reasonably manageable chronic illness, rather like diabetes or asthma.

17
 2-

"Safe" Doesn't Always Mean Safe

When the FDA approves a drug as "safe and effective," it does so based on
data obtained from clinical trials involving several thousand individuals.
Trials involving a few thousand people are a good way to pick up common
side effects, the kind that happen to, say, one user in 10, or 20, or 100.

But many drugs have side effects -- some potentially quite serious -- that
occur much less frequently. If a side effect happens to one user in 10,000 or
50,000, it may not turn up at all during the drug's clinical trials. It may take
several years after the drug has been approved for researchers to realize that
the drug has additional rare side effects.

All drug use should be monitored closely. But the newer the drug, the closer
this surveillance should be because chances are that one or more side effects
remain to be discovered.
3-
Drug Slows Alzheimer's Decline
June 5, 1998

Evidence is mounting that the new Alzheimer's drug, metrifonate, stems

mental decline in those with mild to moderate Alzheimer's disease, a new
study shows.

In a 26-week study, researchers at the Washington University School of

Medicine in St. Louis gave 334 Alzheimer's sufferers either metrifonate or a
placebo. Comparing the groups' cognitive abilities, daily function, and
behavior, those who took the drug remained stable during the study's 6
months, while those taking the placebo declined, said researcher John C.
Morris.

Metrifonate also helped control the hallucinations and agitation many people
with Alzheimer's experience.

Metrifonate, from Bayer Pharmaceutical Division, is not yet approved as an

18
Alzheimer's treatment, but the company has filed an approval petition with
the Food and Drug Administration based on previous studies that showed a
similar slowing of mental decline. Previous studies have also shown that
metrifonate helps control the behavior problems associated with
Alzheimer's.

Source: Neurology (1998) 50:1222-1230

4-
Who Chooses Alzheimer's Drugs? Those in the Earliest Stages
September 8, 1998

The drug, donepezil (Aricept), and vitamin E both do a fairly good job of
slowing the progression of Alzheimer's disease. Some people with
Alzheimer's and their caregivers are eager to use them. Others are not. Paul
Kettl, M.D., acting chair of psychiatry at Penn State University surveyed 60
people with Alzheimer's admitted to Hershey Medical Center about their use
of these treatments.

He found that 28 took the drugs while 32 did not. There were no differences
in decision-making based on the affected individual's age or sex. The only
thing that mattered was how far the disease had progressed.

People in the earliest stages of Alzheimer's were much more likely to be

treated than those with more advanced disease.

In the early stages of Alzheimer's, affected individuals almost always live at

home or with a caregiver. Treatment helps preserve their remaining
cognitive function and makes life easier for their caregivers. But once people
with Alzheimer's have more advanced disease, they have less cognitive
function left to preserve and are more likely to live in residential care. The
benefits of treatment decline, and they are less likely to be treated.

19
Source: American Journal of Alzheimer's Disease

5-
Newly Discovered "Parent" Brain Cells Raise Hope for
Alzheimer's Treatment
March 24, 1999

Swedish scientists have discovered the "parent" brain cells that give rise to
all other brain cells. These "neural stem cells" hold tremendous interest for
researchers because, if they could be manipulated, it's possible that they
might be used to repair a broad range of neurological conditions, among
them: Parkinson's disease, spinal cord injuries, and Alzheimer's.

The Swedish biologists at the Karolinska Institute in Stocholm worked with

rat brains. But now that the hiding place for neural stem cells has been
discovered in a lower mammal, researchers voice confidence that they can be
found in the same place in humans, or close by.

Until recently, researchers believed that the brain did not add new cells after
becoming mature, and therefore, had no stem cells. But in the last few years,
studies have shown that the brain is much less static. Brain cells can be
coaxed into dividing, and even changing into different types of brain cells.
These findings strongly implied that the brain must have parent stem cells.
The Swedish team is the first to find them.

The scientists hope to develop methods to develop the stem cells into mature
cells that can replace damaged cells in the brain. If this works, it would be
possible in the future to reseed damaged brains with cells from the person's
own brain, thus eliminating all transplant-rejection problems.

Source: New York Times

20
Treatment A New Alzheimer's Drug Shows Promise for Tasks
of Daily Living
May 16, 1999

A new Alzheimer's medication appears to outperform the two

currently approved medications in supporting patients' ability to
perform routine tasks of daily living, according to a new report.

The drug, eptastigmine, was recently tested by researchers with the

company that makes it, Mediolanum Farmaceutici, of Milan, Italy.

Eptastigmine was given to 491 people with Alzheimer's for 24 weeks

through study centers in Europe and the United States. All of them
met standard diagnostic criteria for "probable Alzheimer's disease."

Eptastigmine slowed cognitive deterioration about as well as the two

approved drugs, tacrine (Cognex) and donepezil (Aricept). But
eptastigmine showed greater benefit than the other two drugs in
helping people with Alzheimer's maintain their ability to perform
tasks of daily living: dressing, washing, eating, etc.

It's not yet clear why eptastigmine preserves these abilities, and the
study must be replicated by independent researchers before it can be
considered valid. Nonetheless, if this report is correct, eptastigmine
could prove a valuable addition to current drugs.

Source: Lancet, Oct 24, 1998; 352:1347.

Antioxidants
We humans need oxygen to live, but oxygen also has a downside. In the
body, some oxygen molecules become so highly chemically reactive that
they disrupt other body processes. These troublemaker molecules are called
"free radicals," and many scientists believe that the damage they inflict
(oxidative damage) is at the root of both cancer and heart disease. (Smoking
and a high-fat diet greatly increase the number of free radicals in the blood.)

Free radicals also contribute to the development of Alzheimer's disease. The

destructive action of free radicals fits neatly with two other risk factors for

21
Alzheimer's -- one form of the gene for apolipoprotein E (ApoE4) and beta-
amyloid. The ApoE gene controls synthesis of apolipoprotein, which
transports cholesterol in the blood. People with two copies of the ApoE4
variety of this gene have higher concentrations of low-density lipoprotein,
(LDL, so-called "bad cholesterol" because it increases risk of heart attack).
High LDL levels have also been linked to Alzheimer's risk. In addition, high
LDL levels also seem to favor deposition of beta-amyloid, the major
component of the senile plaques characteristic of Alzheimer's. Beta-amyloid
appears to react with the cells that line blood vessels in the brain to produce
excessive quantities of free radicals, which damage brain tissue even more.
Brain tissue is highly susceptible to free radical damage because, unlike
many other tissues, it does not contain significant amounts of protective
antioxidant compounds. (Lancet, 349:1189, 4-26-97)

Fortunately, certain nutrients -- antioxidants -- can prevent the oxidative

damage free radicals cause. Antioxidant nutrients include:vitamin A, vitamin
C, vitamin E, the mineral selenium, and vitamin A's close chemical relatives,
the carotenoids, among them beta-carotene. These nutrients are abundant in
plant foods, and many studies show that as fruit and vegetable consumption
increases, risk of cancer decreases.

A few studies have investigated the effects of antioxidants on Alzheimer's

disease. Results to date have been intriguing:
• Czech researchers gave the antioxidant drug selegiline to 173 people
with mild to moderate Alzheimer's disease. After six months, their
memory improved significantly.

• In another study, selegiline enhanced the benefits of tacrine (Cognex),

one of the two drugs currently approved for Alzheimer's treatment.
Estrogen
Compared with men, women are at greater risk of developing Alzheimer's
disease. But recent studies show that they also have a treatment option
unavailable to most men -- the female sex hormone estrogen, which helps
prevent, delay, and treat Alzheimer's disease.

Several studies show that women who take estrogen after menopause have
an unexpectedly low incidence of Alzheimer's disease. Among women with
Alzheimer's, those taking estrogen suffer less severe symptoms and slower

22
mental deterioration. In addition, animal studies show that estrogen
improves blood circulation through the brain, and stimulates nerve cell
growth in areas of the brain affected by Alzheimer's.

These findings are summarized in a report published in the July 1996

Journal of the American Geriatric Society by Stanley Birge, M.D., a
geriatrician at the Washington University School of Medicine in St. Louis.
Birge calls these estrogen findings "terribly exciting" and potentially "among
the most promising recent discoveries about treating Alzheimer's."

Estrogen boosts the production of acetylcholine, a key chemical

(neurotransmitter) involved in the transmission of nerve impulses across the
tiny gaps between nerve cells (synapses). Estrogen also impedes the
deposition of beta-amyloid, the protein involved in the characteristic plaques
of Alzheimer's disease. In addition, estrogen improves blood flow through
the brain, and enhances verbal abilities of postmenopausal women who take
hormone replacement therapy. Estrogen also helps maintain the integrity of
the hippocampus, a structure in the brain involved in memory. (Kawas, C. et
al. "Treating Alzheimer's Disease: Today and Tomorrow," Patient Care,
Nov. 15, 1996, 62-83.)

Several lines of evidence show that estrogen helps both prevent and treat
Alzheimer's disease:
• Several epidemiological studies show that taking estrogen reduces
women's risk of Alzheimer's disease. (Paganini-Hill, A. et al. "
Estrogen Deficiency and Risk of Alzheimer's Disease," American
Journal of Epidemiology (1994) 140:256.) Notably, New York City
researchers investigated Alzheimer's risk among 1,124 elderly women.
During the follow-up period, the disease developed in 14.9 percent of
them. Among women who had never used estrogen, the figure was
16.3 percent, while only 5.8 percent of estrogen users developed
Alzheimer's. Among estrogen users, risk decreased with hormone use
longer than one year. (Tang, MX et al. "Effect of Estrogen During
Menopause on Risk and Age at Onset of Alzheimer's Disease," Lancet
(1996) 348:429.)

• In a 30-week study of 318 women with mild to moderate Alzheimer's

disease, all participants took tacrine (Cognex), one of only two drugs
currently approved to treat the disease, and some also took estrogen

23
 replacement therapy. Compared with those on tacrine only, the women
taking tacrine plus estrogen fared better on a number of cognitive
measures. (Schneider, LS et al. "Effects of Estrogen Replacement
Therapy on Response to Tacrine in Patients with Alzheimer's
Disease," Neurology (1996) 46:1580.)

• In an eight-week study of 12 Tacoma, Washington, women with mild

to moderate Alzheimer's, all the women received skin patches -- half
that released estrogen into the blood, and that contained a placebo.
"The estrogen had a rapid effect," said Sanjay Asthana, M.D., who
presented the results at a meeting of the Society for Neuroscience.
"Within a week, the women on estrogen showed improvement." By
the end of the study, the estrogen users' cognitive test scores had
almost doubled. The more estrogen the women absorbed, the greater
their mental improvement. (New York Times, Nov. 21, 1996)

• Finally, as part of the 38-year Baltimore Longitudinal Study of Aging,

researchers from the National Institute on Aging assessed 16 year's
worth of medical records for 514 postmenopausal women. They found
that compared with women who had never taken estrogen, those who
had were 54 percent less likely to develop Alzheimer's disease.
(Stephenson, J. "More Evidence Links NSAID, Estrogen Use with
Reduced Alzheimer's Risk," Journal of the American Medical
Association (May 8, 1996) 275:1389.)
In addition to helping prevent and treat Alzheimer's disease, a great deal of
research shows that the sex hormone also helps prevent heart disease,
women's leading cause of death, and osteoporosis, bone-thinning that can
lead to serious fractures.

But for all its benefits, estrogen also carries some risks. It increases breast
cancer risk an estimated 20 to 30 percent, and also increases uterine cancer
risk if the woman takes it without another sex hormone, progesterone.
Cholinesterase Inhibitors
Most people think of the nervous system as the body's electrical wiring. This
is correct -- but only up to a point. Nerve cells transmit impulses much like
wires transmit electricity. But unlike wires, which are continuous filaments,
nerve fibers are discontinuous. Nerve cells do not touch one another. They
have microscopic gaps between them called synapses. Nerve impulses must

24
jump these gaps to proceed on their way. They do it with the help of special
chemicals called neurotransmitters. As a nerve impulse passes through a
nerve cell, it activates the release of neurotransmitters into the cell's
synapses, allowing the impulse to jump the gap, and proceed on its way.
Once the impulse crosses the synapse, special enzymes eliminate the
neurotransmitter, leaving the cell and synapse ready to react to the next
impulse. One important neurotransmitter is acetylcholine (a-SEE-tull-KOH-
leen).

During the late 1970s, researchers discovered that people with Alzheimer's
disease suffer a loss of acetylcholine from their synapses. This observation
fueled theories that Alzheimer's might disrupt the synthesis of acetylcholine,
or that the disease triggers overproduction of the enzyme that eliminates it,
acetylcholinesterase -- generally known as cholinesterase. Scientists
speculated that drugs that either increased acetylcholine or inhibited
cholinesterase might help treat Alzheimer's disease.

Cholinesterase inhibition has yielded the most promising results so far. The
two drugs currently approved for treatment of Alzheimer's -- tacrine
(Cognex) and donepezil (Aricept) -- are both cholinesterase inhibitors. They
do not cure Alzheimer's disease, but when they work, they slow its cognitive
decline.

Several additional cholinesterase inhibitors are also being developed, and a

few, for example, Promem (metrifonate from Bayer Corporation
Pharmaceutical Division), are close to Food and Drug Administration (FDA)
approval. (Bayer Corporation Pharmaceutical Division is the provider of an
unrestricted educational grant to Alzheimers.com).
• Promem (metrifonate from Bayer Corporation). ProMem is currently
under review by the FDA for the treatment of mild to moderate
Alzheimer's disease. In addition to improving cognition and the
performance of activities of daily living, clinical trials have shown
that it also helps minimize the disruptive behavior common among
Alzheimer's sufferers.

In a six-month study by researchers at the University of California, at

Los Angeles, Alzheimer's Disease Center, 408 people with mild-to-
moderate Alzheimer's were given either a placebo or metrifonate (30
to 60 mg once a day based on their weight). Cognition tests showed

25
 that those taking the drug improved significantly. In addition, they
also experienced significantly fewer typical Alzheimer's psychiatric
and behavior problems, notably less depression, lethargy, and apathy,
and fewer hallucinations.

Researchers at the Washington University School of Medicine in St.

Louis confirmed those results in a six-month study involving 334
Alzheimer's sufferers who took either metrifonate or a placebo. In the
placebo group, cognitive function declined significantly, but among
those taking metrifonate, it remained stable. In addition, metrifonate
users suffered less agitation and few hallucinations.

Metrifonate is given once a day. Common side effects include: nausea,

diarrhea, and leg cramps.

Bayer petitioned the FDA to approve metrifonate in 1997. The

application is still pending.

• Tacrine (Cognex, from Parke-Davis). Tacrine is one of only two

drugs currently approved for treatment of Alzheimer's disease. The
FDA approved it largely because a 30-week study showed that high
doses improve cognition in people with mild to moderate Alzheimer's
disease (Knapp, MJ et al. "A 30-Week Randomized Controlled Trial
of High-Dose Tacrine in Patients with Alzheimer's Disease," Journal
of the American Medical Association. (1994) 271:985). It has also
shown some benefit for those with advanced Alzheimer's.

But since its approval, clinical experience has been disappointing.

Depending on the study, tacrine helps only 20 to 40 percent of those
who take it (Kawas, C. et al. "Treating Alzheimer's Disease: Today
and Tomorrow," Patient Care, Nov. 15, 1996, 62-83.) At this point,
doctors cannot predict who will respond to tacrine, to what extent, and
for how long. Tacrine may help somewhat, but only for a minority of
people with Alzheimer's diseases.

People taking tacrine typically start with 40 milligrams per day

(md/d), with dosage rising incrementally at six-week intervals to 80,
120, and 160 mg/d. However, some clinicians say the dose can be

26
 increased more rapidly.

Tacrine has significant side effects, including nausea and vomiting.

But the one that has caused the most concern is the possibility of liver
damage. Tacrine substantially increases levels of the liver enzyme,
alanine transaminase (ALT) -- to three to five times normal levels.
The rise in ALT typically begins about six weeks into treatment. The
long-term effects of high ALT levels remain unclear, but doctors
prescribing tacrine generally advise blood tests to assess ALT level
every two weeks, with a reduction in dose if levels rise beyond about
five times normal. The person with Alzheimer's may resist the
periodic blood tests that the use of the drug requires.

Finally, the cost of tacrine is an issue. The drug costs about $125 a
month. However, a recent study by the San Francisco-based
Technology Assessment Group (TAG) shows that despite its limited
effectiveness, tacrine is cost-effective for those who respond to it.
TAG estimated that the lifetime cost of tacrine plus medical
monitoring of its use would be around $2,600. However, the drug is
estimated to save an estimated $9,300 in lifetime medical costs
($114,500 with tacrine, $123,800 without it). Finally, to the extent that
a good response to tacrine keeps people functional longer, it also
shortens nursing home stays. Without tacrine, the typical Alzheimer's
sufferer spends 2.7 years in a nursing home; with it, 1.5.

Tacrine may be cost-effective for the minority of people who respond

to it, but because of its limited effectiveness and side effects, the
enthusiasm that greeted its approval has cooled considerably.

• Donepezil (Aricept, from Pfiser-Eisai). The FDA approved this

cholinesterase inhibitor in November 1996, based in part on a study
reported at the spring 1996 meeting of the American Academy of
Neurology in San Francisco. In the 24-week study, 450 Alzheimer's
sufferers were divided into two groups. One received a placebo; the
other either 5 or 10 mg/d of donepezil. Compared with the placebo
group, those taking donepezil showed significant improvement in
cognitive skills and dailfunctioning.

27
 Donepezil is better targeted than tacrine. It affects only acetylcholine
in the brain, preventing its breakdown, while tacrine affects related
compounds throughout the body, according to Dr. Sharon Rogers,
research chief at the drug's manufacturer, Easai America. Donepezil's
more targeted action means fewer side effects. Like tacrine, donepezil
possible side effects include: nausea, vomiting, and diarrhea. But
unlike tacrine, donepezil does not cause liver enzyme abnormalities.
Users need not have regular liver-function tests.

In addition, donepezil is taken only once a day. Tacrine must be taken

four times a day.

Like tacrine, donepezil does not work for everyone who uses it. As of
February 1997, the response rate remains unclear.

• ENA-713 (from Sandoz). A study of this cholinesterase inhibitor was

presented at the Fifth International Conference of Alzheimer's Disease
and Related Disorders in Osaka, Japan, in July 1996. The six-month
trial involved 699 people with Alzheimer's, half of whom took the
drug and half a placebo. Those on ENA-713 showed significant
cognitive improvement. Side effects included: nausea, vomiting,
diarrhea, and loss of appetite, but no liver-enzyme abnormalities.

• Other cholinesterase inhibitors in development include: physostigmine

SR (from Forest), NXX-066 (from Astra Arcus), and galanthamine
(from Janssen).

• Meanwhile, drugs that boost levels of acetylcholine are also in

development, among them: xanomeline (from Eli Lilly), milameline
(from Parke-Davis), SB-202026 (from SmithKline Beecham), AF-
102B (from Snow Brand Products), and ABT-418 (from Abbott).
Other Treatments
WARNING: These treatments have not been approved by the U.S. Food and Drug Administration
(FDA), and have not undergone FDA-approved double-blind studies.

28
Ginkgo
Ginkgo (Ginkgo biloba), a living relic of the Dinosaur Age, is the oldest
surviving species of tree on Earth. Poetically, it helps the oldest surviving
people. An extract of ginkgo leaves helps prevent and treat many conditions
associated with aging: stroke, heart disease, impotence, deafness, blindness,
and memory loss. Recent studies show it also helps treat Alzheimer's
disease.

Available over-the-counter at health food stores, ginkgo is only starting to

catch on in the U.S., and is not well-known among American physicians. But
in Europe, where most of the research has taken place, ginkgo is widely
prescribed for the elderly, accounting for sales of more than $500 million a
year.

Medical interest in ginkgo stems from the herb's ability to interfere with the
action of a substance the body produces called platelet activation factor
(PAF). Discovered in 1972, PAF is involved in an enormous number of
biological processes. By inhibiting PAF, ginkgo has been shown to have
enormous medical potential, particularly in conditions associated with aging.

Unless otherwise noted, the information in this section comes from two
European collections of ginkgo studies: Ginkgo Biloba Extract:
Pharmacological Activities and Clinical Applications (Elsevier, Paris, 1991),
and Rokan Ginkgo Biloba: Recent Results in Pharmacology and Clinic
(Springer-Verlag, Berlin, 1988).

Cerebral insufficiency/Memory. Whether or not people develop

Alzheimer's disease, with age, blood circulation through the brain declines.
When this becomes significant, the condition is known as cerebral
insufficiency. It causes memory lapses, problem-solving difficulties, and
other cognitive deficits, but does not progress to dementia. Dozens of
European studies demonstrate that ginkgo extract helps restore blood flow
through the brain and reverse cerebral insufficiency.

In one 12-week, double-blind 1994 trial, conducted by researchers at the

Humbloldt University of Berlin, German, 90 elderly people, average age 63,
who had been referred by neurologists for cerebral insufficiency, were
divided into two groups. One took a placebo, the other, a standardized
gingko extract (50 mg three times a day). After three months, the placebo

29
takers showed only minor cognitive improvement, but those taking ginkgo
showed significantly improved memory, concentration, and reaction time.
The ginkgo extract caused no side effects. (Vesper, J. and KD Hansgen.
"Efficacy of Ginkgo Biloba in 90 Outpatients with Cerebral Insufficiency,"
Phytomedicine (1994) 1:9.)

Gingko improves memory not only in elderly with cerebral insufficiency,

but also in younger people with normal brain function. British researchers at
the University of Leeds gave memory tests to eight women (average age 32),
and then gave them a variety of medications -- a placebo, and ginkgo extract
in doses of 120 mg, 240 mg, and 600 mg. The placebo produced no
improvement in memory, but the ginkgo did, with increasing doses showing
increasing benefits. The women's memory improved "very significantly"
after taking the 600 mg dose.

Alzheimer's disease. In a 1996 study, German researchers recruited 156

people with either Alzheimer's disease or multi-infarct dementia, and gave
half of them a placebo, and half a standardized ginkgo extract (120 mg twice
a day). After 24 weeks, compared with the placebo group, those taking
ginkgo showed significant improvement in cognitive function, as measured
by a variety of standardized tests. About 6 percent of the ginkgo users
reported minor side effects: allergic skin reactions, headache, and stomach
upset (Kanowski. S. et al. "Proof of Efficacy of Ginkgo biloba Special
Extract EGb 761 in Outpatients Suffering from Mild to Moderate
Degenerative Dementia of the Alzheimer Type or Multi-Infarct Dementia,"
Pharmacopsychiatry (1996) 29:47.)

In a report released in 1994, the German equivalent of the Food and Drug
Administration endorsed ginkgo for early-stage dementias.

Other uses. European physicians also prescribe ginkgo for:

• Stroke recovery because it improves blood flow through the brain.

• Coronary artery disease. This is the cause of heart attack. It involves

the progressive narrowing of the arteries that nourish the heart.
Gingko helps prevent arterial narrowing.

• Intermittent claudication, similar narrowing of the arteries in the legs.

30
 • Erection impairment caused by lack to blood flow to the penis. Two
studies have shown "significant improvement" in erection capacity
with ginkgo treatment.

• Macular degeneration, deterioration of the retina, the nerve-rich area

in the eye necessary for sight. A year-long double-blind study of 36
intermittent claudication sufferers showed ginkgo produced
"significantly greater pain relief [than standard treatment]."

• Cochlear deafness, hearing loss resulting from decreased blood flow

to the nerves involved in hearing. A double-blind study comparing
ginkgo to standard therapy showed "significant recovery in both
groups, but distinctly better improvement in the ginkgo group."

• Chronic ringing in the ears (tinnitus). A 13-month double-blind study

of 103 chronic tinnitus sufferers showed ginkgo "conclusively
effective." Ginkgo "improved all the patients" taking the herb.

• Chronic dizziness (vertigo). Seventy people with chronic vertigo were

treated for three months with either ginkgo extract or a placebo. At the
conclusion of the trial, 18 percent of the placebo-takers no longer felt
dizzy, compared with 47 percent of those who took ginkgo, a highly
significant difference.

Because ginkgo is not well-known among U.S. physicians, few recommend

it. However, if you'd like to use it, or give it to a loved one, ginkgo extract is
available at most health food stores and supplement shops. The medicinal
chemicals in ginkgo leaves are too dilute to have any effect, so standardized
extracts concentrate them by processing 50 pounds of leaves into 1 pound of
extract -- a 50:1 extract. For dosage, follow package directions. Cognitive
improvement may takes several months to become noticeable. Ginkgo side
effects, if any, are typically minor -- stomach upset, headache, allergic skin
reactions. If any develop, reduce the dose, or stop using ginkgo.

Acetyl-L-Carnitine
Alzheimer's disease is associated with decreased levels of the
neurotransmitter, ac, in the brain. A key ingredient of acetylcholine is the
amino acid, choline. But for reasons that remain unclear, choline

31
supplementation has little effect on Alzheimer's progression.

However, another combination of amino acids, acetyl-L-carnitine, or

carnitine for short, has shown some promise. Carnitine is a nutrient
composed of two amino acids, lysine and methionine. Two studies have
shown that carnitine slows cognitive deterioration in people with
Alzheimer's disease.

In a 1991 Italian study, researchers divided 130 people with Alzheimer's into
two groups. One group took a placebo, the other, a daily dose of 2,000 mg of
carnitine. After one year, both groups showed cognitive deterioration, but
those taking carnitine showed significantly less decline in memory, logic,
verbal skills, and attention to tasks. (Spagnoli, A. et al. "Long-Term Acetyl-
L-Choline Treatment in Alzheimer's Disease," Neurology (1991) 41:1726)

In 1992, Mary Sano, Ph.D., of the Neurological Institute in New York City,
treated 30 people with mild to moderate Alzheimer's disease with either a
placebo or acetyl-L-carnitine (2.5 g per day for three months, then 3 g/day
for three months). At six months, compared with the placebo-takers, the
carnitine group showed significantly less cognitive deterioration. (Sano, M.
et al. "A Double-Blind Parallel Design Pilot Study of Acetyl-Levocarnitine
in Patients with Alzheimer's Disease," Archives of Neurology (1992)
49:1137.)

More recently, in a 1995 study, University of Pittsburgh researchers divided

12 Alzheimer's sufferers into two groups. Five received a placebo, while
seven took 3,000 mg of carnitine daily for one year. Compared with the
placebo group, those taking carnitine showed significantly less mental
deterioration based on the Mini-Mental Status test and the Alzheimer's
Disease Assessment Scale. (Pettegrew, JW, et al. "Clinical and
Neurochemical Effects of Acetyl-L-Carnitine in Alzheimer's Disease,"
Neurobiology of Aging (1995) 16:1.)

Ampakines
Ampakines are a new class of drugs that improve memory. According to
researcher Gary Lynch of the University of California at Irvine, who has
studied ampakines since 1991, they increase cortical brain activity.

Lynch and Gary Rogers, head of drug development at Cortex

32
Pharmaceuticals in Southern California, have developed an ampakine drug,
Ampalex, that increases levels of a specific neurotransmitter in the brain,
AMPA-glutamate. In a recent 16-day animal study, animals not taking
Ampalex scored 50 percent on a variety of memory tests, while those taking
the drug scored 85 percent.

So far in humans, Ampalex has been tested in Germany and Sweden on 54

people, age 21 to 73, with normal brain function. Compared with those not
taking the drug, those using Amaplex scored twice as well on short-term
memory tests.

In November, 1996, Cortex contracted with the National Institute on Aging

to test Ampalex on a small group of people with Alzheimer's disease. Results
are expected in 1998.

Calcium Channel Blockers

As nerve cells die, they lose the ability to regulate the flow of calcium across
their cell membranes. Some researchers speculate that calcium channel
blockers, drugs that effect this minerals flow in and out of cells, may prolong
nerve cell life.

Nerve Growth Factor

This hormone stimulates the growth of the nerve cells that release
acetylcholine, the neurotransmitter that declines in people with Alzheimer's
disease. Some researchers believe that by introducing nerve growth factor --
or a similar compound -- into the brains of people with early Alzheimer's,
they may be able to slow or reverse cognitive deterioration. Unfortunately,
nerve growth factor does not cross the blood-brain barrier, so the hormone
cannot be given orally or by injection.

Aromatherapy Massage

Aromatherapy is an alternative healing art that uses fragrant plant oils

(essential oils) to affect the body. Aromatherapy dates back to ancient Egypt,
and is used today by real estate agents, who advise home sellers to bake
cookies on days the home will be shown to fill the house with an inviting
aroma that says "home."

33
Essential oils are small molecules that quickly reach the brain either by
inhalation or through skin penetration in massage lotions. Their effects on
the body remain largely unexplored, but the few studies that have been
performed have documented a clear correlation between certain fragrances
and mood enhancement. (Knasko, S. and A. Gilbert. "Emotional State,
Physical Well-Being, and Performance in the Presence of Feigned Ambient
Odor," J. of Applied Social Psychology, (1990) 20;1345.)

In 1988, Megan Carnarius, R.N., a Colorado nursing home nurse who cared
for people with Alzheimer's disease, began giving aromatherapy massages to
six people with late-stage Alzheimer's who required antipsychotic
medication to control their behavior problems. After five weeks of twice
weekly, 40-minute massages, none of them needed antipsychotics any
longer.

In 1989, Carnarius became an Alzheimer's nurse at Manor Care Nursing

Home in Boulder, Colorado, and expanded her aromatherapy program. She
began using diffusers, special devices that broadcast fragrances, to spread a
lemon scent around the Alzheimer's unit each morning. "Lemon is refreshing
and helps everyone wake up," she explains.

In the afternoon, she diffuses any of several calming oils around the unit --
chamomile, germanium, lavender, marjoram, rosemary, or ylang-ylang.

She has also recruited students from the nearby Boulder School of Massage
Therapy to give people on the Alzheimer's unit aromatherapy massages
using the calming essential oils. The aromatherapy program has not been
evaluated in a rigorous scientific study, but Manor Care staff generally agree
that it has had a significant positive impact on residents with Alzheimer's.
Behavior problems have declined, and positive social interactions have
increased.

Recently, the program has been expanded to the Alzheimer's units of 13

additional Manor Care facilities, which house more than 450 Alzheimer's
sufferers. In collaboration with Laraine Kyle, R.N., a founder of the
Association for Holistic Aromatherapy, Carnarius has developed an
aromatherapy massage kit containing five calming oils and instructions for
their use.

34
Aromatherapy massage does not improve memory nor slow cognitive
decline, but it improves quality of life for people with Alzheimer's, and as a
result, can play a supportive role in treatment. (Flanagan, N. "Essential Oils
and Aromatherapy for Alzheimer's Patients," Alternative and
Complementary Therapies, Nov.-Dec. 1995, pp. 377-380.)

Even without the use of essential oils, massage helps minimize disruptive
behavior in people with Alzheimer's disease. In a study in three Alzheimer's
care units in British Columbia, 57 people with the disease were divided into
two groups. One received two six-minute massages a day for three days; the
other did not. Despite the brevity of the massages and the short duration of
the study, compared with the control group, the people who received the
massages became less disruptive and wandered less. (Woods, DL et al.
"Effect of Therapeutic Touch on Disruptive Behaviors of Individuals with
Dementia of the Alzheimer's Type," Alternative Therapies, July 1996,
2:4:95.)
Many Caregivers Try Alternative Therapies on Loved
Ones With Alzheimer's
Fifty-five percent of caregivers give at least one alternative therapy to loved
ones with Alzheimer's disease, according to a survey of 101 caregivers by
researchers with the Program on Aging at the University of North Carolina
School of Medicine. (Coleman, LM et al. "Use of Unproven Therapies by
People with Alzheimer's Disease," Journal of the American Geriatric Society

Among the various alternative approaches:

• 84 percent of caregivers gave vitamins to Alzheimer's sufferers.
• 22 percent fed them health foods.
• 11 percent tried herbal medicines
• 9 percent tried so-called "smart pills," over-the-counter products
available at health food stores that claim to aid brain function.
• One caregiver in five had tried three or more alternative treatments.
Two-thirds of the caregivers, who werecruited from the North Carolina
chapters of the Alzheimer's Association, reported that the alternative
treatments produced no improvement in their loved ones, while one-third
said the unconventional approaches had helped "a little."

However, a one-third response rate is what could be expected from treatment

with any placebo. These results suggest that the alternative approaches used

35
in this study have no value in treating Alzheimer's disease.

But the researchers noted that they were not surprised by the popularity of
alternative approaches because conventional medicine currently has so little
to offer in the way of Alzheimer's treatment.
IPA CONGRESS: Aricept Effective, Well-Tolerated For Long-
Term Alzheimer's Treatment

VANCOUVER, BC -- Aug. 17, 1999 -- Study results evaluating patients

with mild to moderately-severe Alzheimer's disease (AD) found that Eisai
Co., Ltd.’s and Pfizer Inc.’s once-daily treatment, Aricept(R) (donepezil
hydrochloride) had beneficial effects on global and cognitive functioning
and activities of daily living over one year.
Researchers presented the results of this randomised, double-blind, placebo-
controlled trial today at a poster presentation at the ninth congress of the
International Psychogeriatric Association.
"This is good news for Alzheimer's disease patients and their caregivers
world-wide," said Bengt Winblad, M.D., department of clinical neuroscience
and family medicine, Karolinska Institute, Sweden. "Aricept offers hope to
those looking for well-tolerated and effective, long-term treatment."
Patients treated with Aricept showed statistically significant results in global
functioning. The Aricept-treated group's mean change from baseline on the
Gottfries, Brane and Steen scale (GBS) total score were statistically
significantly better at Weeks 24, 36 and 52 compared to the placebo-treated
group. Patients treated with Aricept also showed statistically-significant
improvement in cognition and activities of daily living compared to placebo.
When compared to the placebo-treated group's scores, the Aricept-treated
group's average changes from baseline on the Mini-Mental State
Examination (MMSE) were statistically significant at Weeks 24, 36 and 52
and Progressive Deterioration Scale (PDS) total scores at Week 52,
respectively.
This study evaluated the long-term clinical efficacy and tolerability of
donepezil versus placebo over one year in patients (average age 72.5 years)
with mild to moderately severe Alzheimer's disease (AD). The study
recruited 286 patients with possible or probable AD from 28 sites in five
Northern European countries (Denmark, Finland, The Netherlands, Norway
and Sweden). They were randomised to receive either Aricept or placebo for

36
one year. In this trial, 66.9 percent of Aricept- and 67.4 percent of placebo-
treated patients completed the one-year study. Only seven percent of
Aricept- and 6.3 percent of placebo-treated patients discontinued due to
adverse events.
Alzheimer's disease is a progressive, degenerative brain disease that results
in cognitive decline, impaired memory, thinking, behaviour changes, loss of
language, motor skills and activities of daily living (or self-
maintenance skills -- that is, grooming, etc.). Currently, approximately 15
million people suffer from AD world-wide.
Aricept is indicated for the symptomatic treatment of mild to moderately-
severe dementia of the Alzheimer's type. Aricept is well-tolerated, with a
low incidence of side effects, offers convenient, once-daily dosing and can
be taken with or without food. In controlled trials that supported the
approval of Aricept, it was found that the drug's most common side effects
include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and
anorexia. These effects were often mild, transient and resolved with
continued treatment.
People at risk for ulcers should inform their doctor when taking Aricept. In
clinical trials, syncopal episodes have been reported in patients taking
Aricept (two percent versus one percent for placebo). Aricept is clinically
effective at the starting dose of 5-mg/day and the dose can be escalated to
10-mg/day after four to six weeks if clinically indicated.

IPA MEETING: Aricept Effective In Long-Term

Treatment Of Alzheimer's
VANCOUVER, BC -- Aug. 18, 1999 -- Cognition and functional abilities of
patients with mild to moderate Alzheimer's disease (AD) treated with
Aricept (donepezil) are enhanced over an extended period of time compared
to patients treated with placebo, according to study results presented for the
first time at the ninth International Psychogeriatric Association meeting
being held in Vancouver this week.
Aricept, the first and only medication approved in Canada for the treatment
of mild to moderate AD, was also confirmed as having long-term beneficial
effects on patients' activities of daily living over a one-year period.
The long-term effects of Aricept were assessed during a 52-week
multicentre, double blind, placebo-controlled trial, involving 286 patients
with mild to moderate AD in five Northern European countries. These
patients were randomly divided to receive once-a-day Aricept or placebo for

37
one year. The Aricept group received 5 mg of Aricept for 28 days followed
by 10 mg daily for the remainder of the trial.
“This study is unique in that Aricept efficacy and safety were measured
against placebo for one year,” said principal investigator Dr. Bengt Winblad,
professor, department of neuroscience and family medicine at the Karolinska
Institute, Huddinge, Sweden. “These results advance the previously
published data supporting the long term benefit of this drug. They confirm
that the clinical benefits of Aricept are sustained over time and that treatment
is also well tolerated over the long-term.”

Key Results:
-- The observed improvement over baseline in global function was
significant among Aricept-treated patients at weeks 24, 36 and 52 as
measured on the Gottfries, Brane and Steen (GBS) scale.
-- Statistically significant improvement in cognition over baseline was
observed at weeks 24, 36 and 52 weeks in patients receiving Aricept, as
measured by the Mini Mental State Evaluation (MMSE) scores.
-- After one year, at week 52, Aricept-treated patients showed less decline in
activities of daily living (ADL) as measured by the Progressive Deterioration
Scale (PDS) scores.
“This is certainly more good news for Canadian Alzheimer's disease patients
and their caregivers,” said Dr. Sandra Black, head of neurology at
Sunnybrook and Women's College Health Sciences Centre of Toronto and
an AD investigator.
“Alzheimer's disease is not a normal part of ageing. It is a degenerative
disease that can be kept in check or delayed for some time,” Dr. Black
explained. “To give people the best chance to maintain their current level of
activities, treatment should be considered as soon as you think a patient has
AD and preferably early in the disease course.”

“These results are encouraging to document the effects of Aricept over a

longer time period,” said Dr. François Primeau, psychogeriatrician at St.
Mary's Hospital, Montreal. “As with diseases like cancer, we can now
provide patients and their caregivers with an extended quality of life by
delaying or preventing deterioration of their condition. We may not have a
cure but we can significantly impact on the cost of care by delaying
institutionalisation.”

38
The annual cost of caring for patients with Alzheimer's disease in Canada
increases with the severity of the disease. A 1998 study showed that patients
in the early to mild stages of AD cost $9,451 CDN to treat and care for on an
annual basis. In contrast, the cost to treat and care for patients with severe
AD rises four-fold to $36,794 CDN. As a patient's condition deteriorates,
institutionalisation becomes the largest cost component accounting for as
much as 84 per cent of the cost of care, according to the study.
Recently updated Canadian guidelines for the diagnosis and treatment of
Alzheimer's disease recommend that a trial course of Aricept be prescribed
to informed and willing patients with mild to moderate dementia due to
probable AD, whethere is no contraindication.

IPA CONGRESS: Aricept Effective, Well-Tolerated For Long-

Term Alzheimer's Treatment

VANCOUVER, BC -- Aug. 17, 1999 -- Study results evaluating patients

with mild to moderately-severe Alzheimer's disease (AD) found that Eisai
Co., Ltd.’s and Pfizer Inc.’s once-daily treatment, Aricept(R) (donepezil
hydrochloride) had beneficial effects on global and cognitive functioning
and activities of daily living over one year.
Researchers presented the results of this randomised, double-blind, placebo-
controlled trial today at a poster presentation at the ninth congress of the
International Psychogeriatric Association.
"This is good news for Alzheimer's disease patients and their caregivers
world-wide," said Bengt Winblad, M.D., department of clinical neuroscience
and family medicine, Karolinska Institute, Sweden. "Aricept offers hope to
those looking for well-tolerated and effective, long-term treatment."
Patients treated with Aricept showed statistically significant results in global
functioning. The Aricept-treated group's mean change from baseline on the
Gottfries, Brane and Steen scale (GBS) total score were statistically
significantly better at Weeks 24, 36 and 52 compared to the placebo-treated
group. Patients treated with Aricept also showed statistically-significant
improvement in cognition and activities of daily living compared to placebo.

39
When compared to the placebo-treated group's scores, the Aricept-treated
group's average changes from baseline on the Mini-Mental State
Examination (MMSE) were statistically significant at Weeks 24, 36 and 52
and Progressive Deterioration Scale (PDS) total scores at Week 52,
respectively.
This study evaluated the long-term clinical efficacy and tolerability of
donepezil versus placebo over one year in patients (average age 72.5 years)
with mild to moderately severe Alzheimer's disease (AD). The study
recruited 286 patients with possible or probable AD from 28 sites in five
Northern European countries (Denmark, Finland, The Netherlands, Norway
and Sweden). They were randomised to receive either Aricept or placebo for
one year. In this trial, 66.9 percent of Aricept- and 67.4 percent of placebo-
treated patients completed the one-year study. Only seven percent of
Aricept- and 6.3 percent of placebo-treated patients discontinued due to
adverse events.
Alzheimer's disease is a progressive, degenerative brain disease that results
in cognitive decline, impaired memory, thinking, behaviour changes, loss of
language, motor skills and activities of daily living (or self-
maintenance skills -- that is, grooming, etc.). Currently, approximately 15
million people suffer from AD world-wide.
Aricept is indicated for the symptomatic treatment of mild to moderately-
severe dementia of the Alzheimer's type. Aricept is well-tolerated, with a
low incidence of side effects, offers convenient, once-daily dosing and can
be taken with or without food. In controlled trials that supported the
approval of Aricept, it was found that the drug's most common side effects
include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and
anorexia. These effects were often mild, transient and resolved with
continued treatment.
People at risk for ulcers should inform their doctor when taking Aricept. In
clinical trials, syncopal episodes have been reported in patients taking
Aricept (two percent versus one percent for placebo). Aricept is clinically
effective at the starting dose of 5-mg/day and the dose can be escalated to
10-mg/day after four to six weeks if clinically indicated.
New Drug Holds Promise For Brain Disease
NEW YORK, Aug 24 (Reuters Health) -- A new drug under investigation
may one day prevent the death of brain cells due to head injury, Alzheimer's
disease, Parkinson's disease, stroke and other neurologic disorders,
according to preliminary research presented Tuesday at the annual meeting

40
of the American Chemical Society in New Orleans.

Researchers at the Louisiana State University (LSU) Neuroscience Center of

Excellence in New Orleans have discovered how to turn off the genetic
switch that produces excessive amounts of cyclooxygenase-2 (COX-2), a
protein which, in abundance, leads to death or damage in brain cells or
neurons.

"There is no comparable drug on the market. This is a totally new concept,"

lead researcher Dr. Nicolas G. Bazan, director of the LSU Neuroscience
Center of Excellence, told Reuters Health.

"We have found signals within brain cells that result in cell death (and) we
have made a chemical that inhibits these signals," he added. "This chemical
may become a drug applicable to diseases where injury-like processes take
place, producing a damaging protein (that) induces damage and cell death,"
explained Bazan, an Argentine-born scientist.

Basically, injury or disease such as head trauma or stroke triggers a chain

reaction that signals the COX-2 gene to produce genetic material, which, in
turn, produces an abnormally high amount of the COX-2 protein.

"The new drug prevents the production of COX-2 and stops the signaling
process before the genes can be overactivated," Bazan explained. But due to
the testing required to ensure the drug's safety and effectiveness, it will be
several years before the new drug reaches human patients, he noted.

"In our experimental models, our drug is very effective in preventing the
production of COX-2 and halting the signaling process before the genes can
be overactivated," Bazan said.

He added that the findings "may be applicable to neurodegenerative diseases

such as Alzheimer's, Parkinson's, stroke and age-related macular
degeneration" -- an age-related eye disease that is a common cause of
blindness.

"We are achieving a clearer understanding of the mechanisms underlying the

consequences of brain injury. The brain is truly the last frontier of medicine -
- so complex," Bazan commented. "Yet neuroscience research is moving

41
forward at a rapid pace and, as we approach the new millennium, we are
finding new approaches and ultimately cures for diseases, which only a
couple of decades ago held no hope for cure," he added.

Several new drugs on the market, known as super-aspirins, also target COX-
2. The drugs work by selectively blocking the COX-2 enzyme, which is
thought to play a role in causing arthritis pain.
Alzheimer's Drug Helps Patients Maintain Abilities
Longer
NEW YORK, Sep 23 (Reuters Health) -- The drug Aricept (donepezil) helps patients with mild-to-
moderate Alzheimer's disease maintain their ability to perform basic functions such as dressing and feeding
themselves for longer, according to the results of a study.

The one-year study -- the longest yet conducted with this drug -- was presented Thursday at the 12th
annual European College of Neuropsychopharmacology meeting in London. In the study, 431 patients with
mild-to-moderate Alzheimer's disease were randomly assigned to taking daily doses of either the drug or,
for comparison purposes, a placebo ("dummy pill").

Investigators found that although the dementia continued to worsen in both groups of patients, patients
taking Aricept functioned "highly significantly" better over a longer time than those on placebo. Patients on
donepezil maintained functional status about 5 months longer than those on placebo, Pfizer, Inc., of New
York and Esai Co, Ltd., announced in a release of the study's findings.

"Results of this study confirm that treatment with the medication for up to one year allows patients to
maintain their ability to perform activities of daily living such as dressing, eating meals, doing chores, and
enjoying hobbies, and therefore helps them maintain their independence," according to a statement issued
by the drug companies.

Co-investigator Dr. John C. Morris of Washington University School of Medicine in St. Louis told Reuters
Health that the findings "are clinically meaningful." He said that patients who took placebo during the
study have now been switched to active treatment.

A key point in treatment of patients with Alzheimer's might be the stage of disease when treatment begins,
Morris said. There may be a point in the diseasat which the drug may no longer be effective. The big area
of interest now is starting treatment at an even earlier stage of disease. A number of studies will be
investigating that, Morris said.

Adverse effects noted in patients taking Aricept included nausea, diarrhea, insomnia, vomiting, muscle
cramps, fatigue and anorexia. Effects were generally mild and transient, the makers say.

New drugs for Alzehimer’s disease

Alistria burns, eve russell and sean page
British journal of psychiatry (1999), 174, 476-479.

42
Alzheimer’s disease is the most common cause of dementia in older people,
affecting up to 10% of the population over the age of 65 years and three
times that figure in those over the age of 90 years (Hofman et al, 1991), with
a total of about half a million people affected in the UK. The cause of
Alzheimer’s disease is essentially unkonwn, there is no cure for the disease,
the effect on sufferers and families is devastating in personal and emotional
term and the annual cost in nearly 1 billion in the UK (Bosanquet et al,
1998). Based on this background, there should be understandable enthusiasm
at the introduction of new drugs for the treatment of the core features of the
disease (the cognitive deficits, predominantly memory loss) based on
amelioration of the underlying pathophysiology.

Background
A new class of agents, the cholinesterase inhibitors (or anticholinesterases
because of their inhibiting action on acetylcholines-terase, the enzyme
responsible for the breakdown of acetylcholine), is now available for the
symptomatic treatment of Alzheimer’s disease. Other agents may influence
disease progression, such as vitamin E (e.g. Sano et al, 1997) or are
potentially active against both Alzheimer’s disease and vascular dementia
(e.g. propentofylline; Rother et al, 1998). The purpose of this article is to
review briefly these new drugs and outline the implications for
psychiastrists, particularly old age psychiatrists, upon whom the burden of
care is predictably falling.

The clinical manifestations of dementia are threefold: cognitive impairment,

non-cognitive features (psychiatric symptoms and behavioural distrubances),
and activities of daily living (ADLs). Measurement of the effect of drugs has
to take into account the changes is these domains and their relative
importance traditionally has determined which scales are used to assess drug
efficacy. It is widely accepted that cognitive impairment is the primary
abnormality in dementia but the clinical and practical relevance of a
numerical improvement in a memory test has been questioned, leading to the
introduction of global assessments, the most commonly used being the
clinician’s Interview Based Impression (CIBI), which is a simple seven-
point scale measure based on the assumption that a clinician can detect
change in a patient’s condition (Knopman et al, 1994, Schneider et al, 1997).
Specific derivatives aimed at capturing change over time-the Clinicians’s
Interview Based Impression of Change (CIBIC; Leber, 1990) and a scale

43
utilizing care-giver information (CIBIC Plus; Leber, 1990)-are now accepted
as being an essential component of any drug trail.

Non-cognitive features of dementia traditionally were regarded as

epiphenomena (i.e. secondary to cognitive deficits), improvement in which
would take place as a natural consequence of cognitive deficits and treatment
of which was non-specific. For example, a positive effect by a drug being
regarded as an antidepressant and not an antidementia drug, even if a
positive effect on cognition was demonstrated. Problems in ADL are
categorized as basic (e.g. eating, toiletting, washing/dressing) or
instrumental (more complex, such as cooking, shopping and handling
finances). The Committee for Proprietary Medicinal Products (CPMP, 1997)
has produced guidelines recommending that two or three areas of dementia
should be assessed to demonstrate efficacy-cognitive function and either a
global rating or ADL.

Tetrahydroaminoacridine (Tacrine)
Tetrahydroaminoacridine (tacrine) was the first of the new agents to be
introduced and was licensed in the USA, Canada and parts of Europe in
1993. It improved cognitive function in up to 30% of people with
Alzheimer’s disease tested over a six-month period in doses of up to 160 mg
per day. Five crossover trials and five parallel group trials have been
published on the efficacy of tacrine (Glennie, 1997) – modest efficacy
overall and minor improvement in cognitive function were seen in only
three. Preipheral cholinergic side-effects (such as nausea, vomiting and
diarrhoea) were seen in one-fifth of patients but liver toxicity was more
serious, with 40% of patients having raised hepatic transminase levels
(severe in 2%) and necessitating blood monitoring of liver function tests for
the first few months of treatment. In view of the high level of side-effects,
tacrine cannot be recommended for routine use. The drug was not originally
grated a licence in the UK but was approved at the same time as donepezil.

Donepezil hydrochloride
The development of a drug with a similar efficacy profile to tacrine but free
of side-effects was a waited and donepezil hydrochloride seemed to satisfy
this criterion. As a piperidine-based anticholinesterase, is does have the same
potential for liver toxicity as the acridine-based compound, tacrine. It was
licensed for use in the symptomatic treatment of mild to moderate
Alzheimer’s disease in the UK on 17 March 1997. At the time of writing,

44
there have been four published trials of donepezil a Phase II randomized
controlled trial (Rogers & Friedhoff, 1996) with an open-label extension
(Rogers et al, 1998a,b) – all of which have taken place in the USA. A
European and Canadian based multi-country trial has been completed and
the results are in the public domain. Donepezil was licensed at a stage when
only the Phase II trial had appeared in a peer-reviewed journal, although data
on the other trials were made available to the regulatory authorities. All three
studies have demonstrated the benefits of denepezil compared to placebo.
The Phase II study Rogers & Friedhoff, 1996) included 161 patients with
mild to moderately severe Alzheimer’s disease prescribed 1, 3 or 5 mg of
active drug or placebo and found a statistically significant improvement in
the ADAS-Cog score (cognitive sub-scale of the Alzheimer’s Disease
Assessment Scale; Rosen et al, 1984) in patients on 3 and 5 mg compared
with placebo. No difference was found with the other measures. Rogers et al
(1998a) reported that cognitive function (ADAS-Cog), ADL and global
functioning (CIBIC) improved in 473 patients taking 5 or 10 mg compared
with placebo, but with no difference between drug doses. The improvement
returned to the level of the placebo group after a six-week washout. Rogers
et al (1998b) reported a 12-week study on 468 patients and confirmed
significant benefit of the drug over placebo; the European and Canadian-
based multi-centre trial has produced similar positive results (Burns et al,
1999). Side-effect with donepezil are generally of moderate severity,
trnasient and consist of diarrhoea, vomiting, fatigue, muscle cramps and
dizziness. They affect less than 10% of people and are higher with the 10%
of people and are higher with the 10 mg dose.

The magnitude of change (similar all studies) seen with donepezil is an

improvement of around three points on active drug compared with placebo
on the ADAS-Cog scale, which is highly statistically significant (P<0.0001).
to look at it another way, 42% of patients on placebo had worse cognitive
function at the end-point compared with 20% on donepezil. An improvement
of seven points on the ADAS-Cog scale is regarded as being of clinical
significance; on this basis, 8% on placebo, 15% on 5 mg and 25% on 10mg
improved. On the CIBIC, 11% improved in the placebo group compared
with 25% on 5 mg and 25% on 10mg. The recommended drug dose is to
start with 5 mg per day and titrate after a minimum of one month to 10mg. In
the UK, the cost of the drug is 68.32 for 28 5 mg tablets and 95.76 for 28 10
mg tablets.

45
Rivastigmine
Rivastigmine was licensed on 12 May 1998 in the European Community for
the treatment of mild to moderately severe Alzheimer’s disease. Compared
with donepezil, there is a larger patient database on which the introduction
of the drug was based. A specific programme of studies (the ADENA
programme; Anand & Gharabani, 1996; Novartis website
(http://www.alzheimer-info.com/exelon), 1998) consisted of four pivotal
trials aimed at overcoming the drawbacks of existing studies (i.e. small
numbers of patients, short duration of treatment and restrictive entry
criteria). Over 2000 patients have been examined with a dose range of 6-12
mg (twice daily administration), previous studies having shown that 4 mg
was ineffective. The magnitude of the effect is similar to that seen with
donepezil. Specific measures of ADL were included in the trials (the
Progressive Deterioration Scale (PDS); de Jong et al, 1989). Compared with
placebo, 21v. 12% improved on the CIBIC Plus and 26v. 17% improved on
the PDS. Symptoms on rivastigmine included anorexia, nausea, dizziness,
vomiting, appetite and weight loss. It is not, like donepezil, contraindicated
in asthma. The recommended drug dose is to start at 1.5 mg twice daily with
the therapeutic dose between 6 and 12 mg. In the UK, the cost of the drug is
31.50 for 28 tablets regardless of size (1.5, 3, 4.5 or mg), giving a monthly
price of 63 for 12 mg per day.

Other drugs
A dose-finding study of metrifonate (Morris et al, 1998) demonstrated the
efficacy and safety of the drug in patients with Alzheimer’s disease,
showing improvements in ADAS-Cog and the CIBIC. Morris et al (1998)
description a 26-week double-blind treatment trial followed by an 8-week
placebo extension on 408 patients with Alzheimer’s disease, of whom over
80% completed the trial in the active treatment was found in theADAS-Cog
on an intention-to-treat basis. In addition, a specific beneficial effect was
found in terms of non-cognitive features as measured by the
Neuropsychiatric inventory (NPI; Cummings et al, 1994). The beneficial
effect of the drug on non-cognitive features of dementia is novel. McKeith
(1998) described an international study with 605 patients over 26 weeks in
doses of 40-80 mg per day. On an intention-to-treat basis, the drug showed
clear benefit over placebo on cognitive performance and global function.
There are currently safety concerns about metrifonate.

46
Other anticholinesterase agents are being tested (such as galanthamine and
slow-release physotigmine, eptastigmine, ibedenone, zifrosilone and
quilostigmine), as are cholinergic muscarinic agonists (e.g. melamiline and
xanomeline) and precursor loading agents (acetyl-l-cartinine). Non-
cholinergic treatments include; propentofylline, an endenozyne reuptake
(phospho-diesterase) inhibitor that, it is climed, modulates mechanisms in
Alzheimer’s disease and vascular dementia-cell activation, increased
production of cytokines, free radicals and glutamate – with benefits seen in
901 patients with Alzheimer’s disease and 359 patients with vascular
dementia (Rother et al, 1998); memantine, a modulator of the
glutamatergic system that modulates the cytotoxic effects of excitatory
amino acids and has been shown to be of benefit in both Alzheimer’s disease
an vascular dementia (Gortelmeyer et al, 1993); vitamin E and selegiline
(Sano et al, 1997), alone and in combination, which delay the progression of
Alzheimer’s disease; Ginkgo biloba (Le Bars et al, 1997), which has been
shown to produce benefit in one study; Cox-2 inhibitors (drugs with an anti-
inflammatory action), which are being tested; and calcium channel blockers
(e.g. sabeluzole and nimodipine), which have been used. Qestrogenes also
are being tested as potential agents for the prevention of Alzheimer’s disease
(Burns & Murphy, 1996).

Managed introduction-clinical guidelines

Guidelines have been used to manage the introduction of the new drugs for
the treatment of Alzheimer’s disease (e.g. Lovestone et al, 1997). They
define diagnostic criteria for Alzheimer’s disease, suggest clinically relevant
inclusion and exclusion criteria based broadly, should be agreed locally with
general practitioners, pharmacists, local purchasers of health care and
specialists in the management of Alzheimer’s disease. Al with many other
drugs, there is significant variation between different areas of the country
and the implementation of guidelines (Harvey, 1999). Many purchasers of
health care remain to be convinced of the usefulness of prescribing these
drugs in dementia, and the tone of the two articles in the influential Drugs
and Therapeutics Bulletin review of donepenzil reflects this attitude
(Anonymous, 1998, 1999).

The UK Government’s Standing Medical Advisory Committee (SMAC,

1998) has produced guidelines on the treatment of Alzheimer’s disease and
recommends that treatment should be initiated and supervised by a specialist
familiar with the management of Alzheimer’s disease and that, generally

47
speaking, the characteristics of patients selected for treatment should be the
same as those in drug trials. Treatment should be assessed after 12 weeks
and continued only if there is clear evidence of benefit, a judgement
informed by the application of recognized objective tests.

Clinical Experience
Our clinical experience in south Manchester is that the drugs were
introduced without additional funding using a locally agreed protocol
formulated by primary care, hospital specialists and pharmacists. The criteria
are similar to those described in the SMAC guidelines. Prescribing is
initiated by consultants in old age psychiatry in the setting of a specialist
multi-disciplinary domiciliary clinic. Treatment is targeted towards patients
with mild to moderate Alzheimer’s disease supported by radiological
evidence of the absence of vascular disease. Measurements of efficacy in the
three domains of cognitive function, ADL and non-cognitive features of
Alzheimer’s disease are made before the start of treatment and at three-
monthly intervals thereafter.

Early experience of donepezil is similar to that of the drug trials in respect of

the change in cognitive function, with about half of patients showing
improvement at six months and two-thirds of the remainder failing to show
the expected deterioration. Of more clinical importance are the striking
improvements in non-cognitive features and ADL in some patients.
Moreover, their carers describe marked changes to their own quality of life
by no longer having to cope, for example, with a spouse or parent
hallucinating or wandering at night. Many carers remark that patients appear
brighter and more interested in their surroundings. The cost benefit of such
changes has been questioned but the benefit to patients and carers is clear to
them.

As might be expected, when the drug is introduced into clinical practice with
patients experiencing medical comorbidity, the adverse effect profile is
worse than that seen in the trial data. Our initial protocol titrated all patients
on donepezil up to 10 mg after a month and, perhaps as a result of this
relatively quick titration (albeit that given in the data sheet), the frequency of
adverse effect was high. Patients now receive 5mg and side-effects are
usually mild and self-limiting.

48
Rivastigmine has been used less often but, as with donepezil, we have seen
striking effects on non-cognitive features. Patients who have failed to
tolerate donepezil appear to tolerate rivastigmine at a therapeutic dose and
medical comorbidity seems to be less of a problem than with donepezil,
particularly in relation to chronic obstructive airways disease and asthma.
However, the twice daily dosage is a problem for patients without a carer,
with whom we struggle to ensure compliance even on once daily donepezil.

Overall, experience of these drugs has been very positive. Sixty-two patients
have been started on treatment (3:1 in favour of donepezil) and
approximately one-third (for each drug) have stopped treatment because of
side-effects, intercurrent illness or lack of benefit. The changes seen in the
ratings parallel those reported inclinical trials, although responses vary
greatly between patients (Dening & Lawton, 1998). Early and frank
discussion at the start of treatment with patients and carers, with an agreed
trial of treatment and discussion of the results, has ensured that we have
experienced no problems with stopping the drugs if patients are not
receiving any benefit from them.

The Future
New drugs for Alzheimer’s disease are not cures-their effects are probably
best described as modest. However, for the first time, symptomatic
improvement in cognitive function in Alzheimer’s disease is possible. Fear
of the cost involved was calculated speedily in people’s minds simply by
multiplying the numbers of patients with dementia in the UK (800.000) by
the cost of the drug per year (1000); this prompted a knee-jerk reaction
against these drugs, masquerading as protection of public funds in the face
of minimal clinical improvement. More pragmatic trials are needed,
emphasized by the recent call for proposals from the Health Technology
Assessment programme. The AD2000 trial in the West Midlands is currently
underway. In practice, not everyone with dementia has Alzheimer’s disease,
not everyone with Alzheimer’s disease has mild to moderate disease and
even then not everyone will be suitable. Patients and their families may not
even want the drugs. Improvements in patients may cause problems of their
own, such as the desire to drive again as a result of improved memory and
concentration. All the thoughtful clinical would ask for would be that the
medication be available and be introduced in a responsible fashion using
agreed clinical guidelines and subject to audit. One would seek parity with
the controls and restrictions placed on other newly introduced agents for

49
other conditions. The cost of the drugs may be high, but the human cost of
dementia is infinitely higher.

50
MISCELLANEOUS
Medical News
August 1, 1999
Death Rate Higher for Alzheimer's Patients Living in Nursing Homes
A new study concludes that Alzheimer's patients cared for in nursing homes have an increased
risk of dying if they are older, male, malnourished, or are physically impaired. Researchers at
Brown University in Providence, Rhode Island, examined data on nearly 10,000 Alzheimer's
patients in Medicare/ Medicaid-certified nursing homes to reach their conclusions. The study
found that roughly half of Alzheimer's patients in nursing homes died within two years of
admission -- a rate about twice as high as elderly patients who do not have Alzheimer's. It was
further found that being elderly and male increased the risk of death by over 80 percent, impaired
basic functions (walking, eating, and self-care) increased the risk of death by 41 percent, and
malnutrition increased the risk by 31 percent. Other factors less strongly linked to increased
mortality risk in this patient population included: the presence of pressure sores, diabetes, or
heart disease. Results of the analysis are reported in the "Journal of Neurology, Neurosurgery
and Psychiatry" (1999;67:59-65).

© Mediconsult.com 08/01/99

August 1, 1999
Demented Stroke Patients Less Likely to Receive Drug Therapy
A recent report suggests that stroke patients with dementia are less likely than other stroke
victims to receive standard clot- preventing medications such as aspirin or warfarin. (Note: such
drugs can reduce the risk of stroke recurrence.) Researchers at the Columbia University College
of Physicians and Surgeons, in New York, studied 272 ischemic stroke victims over the age of 60
to collect data. It was found, overall, that 11 percent of patients did not receive clot- preventing
therapy by the time they left the hospital and that demented patients were 2.5-times more likely to
not receive the drugs, compared to non-demented patients; about 36 percent of patients not
given aspirin or warfarin had dementia, while only 16 percent of patients given the drugs were
diagnosed with dementia. Authors note that the lack of anticoagulant therapy was also linked to
discharge to a long-term care institution and to difficulty in walking. Reported in the "Journal of
the American Geriatrics Society" (1999;47:824-829).

© Mediconsult.com 08/01/99

August 1, 1999
Experimental Vaccine Shows Promise for Alzheimer's Victims
Researchers have reported promising results from animal trials of an experimental vaccine
against Alzheimer's disease. Researchers at Elan Pharmaceuticals, in South San Francisco,
California, injected nine genetically engineered mice bred to develop Alzheimer's with a vaccine
containing bits of the protein amyloid-beta to collect data. It was found the seven of the nine mice
did not develop the amyloid plaques that characterize Alzheimer's and the vaccine appeared to
prevent the nerve cell damage and brain inflammation typical of the disease. It was further found
that administration of the vaccine appeared to reduce amyloid plaques in mice that had already
developed them. Authors note that it is not yet clear exactly how the vaccine works, but speculate
that it triggers the immune system to produce antibodies that attack the deposits of amyloid.

51
Officials at Elan Pharmaceuticals say they hope to begin safety tests of the vaccine in humans by
the end of 1999. The findings are in the journal "Nature" (1999; 400:173-177).

© Mediconsult.com 08/01/99

August 1, 1999
Other Factors May Influence Apo-E4-related Dementia Risk
A new study says that the increased risk for Alzheimer's disease associated with the Apo-E4
gene mutation is more pronounced when other factors, such as diabetes, peripheral vascular
disease and atherosclerosis are present. Researchers at the University of California School of
Medicine, Davis, studied nearly 6,000 healthy people over age 65 during a 5 to 7 year period to
collect data. The study found that those people with both atherosclerosis and the Apo-E4
mutation had more than an eight-fold increased risk for a decline in cognitive function, compared
to those without the mutation or atherosclerosis. Those participants who carried the Apo-E4
mutation and had diabetes or circulation problems in their hands, feet or legs, had a much higher
risk of a decline in memory and mental functioning during the study than those without the gene
or these illnesses. Authors note, however, that 70 percent of participants experienced no decline
in cognitive function during the study period and say the findings suggest that paying attention to
diet and exercising regularly could mitigate many of the possible causes of dementia, even in
individuals with the Apo-E4 mutation. The study is in the Journal of the American Medical
Association (1999;282:40-45).

© Mediconsult.com 08/01/99

July 12, 1999

Remember Your Estrogen
A common complaint as we age is a loss of short-term memory. Where did I leave my car keys?
Did I lock the front door? Researchers from Yale University recently released study findings
indicating that this problem in women may be partially due to a drop in estrogen level, which
occurs with menopause.

Forty-six women, with an average age of 50, were divided into two groups. One group received
estrogen for three weeks and the other a placebo. Then all the women received a functional
magnetic resonance imaging (fMRI) test while performing simple verbal and nonverbal memory
tasks. After a two-week break to allow the estrogen to dissipate from participants' systems, the
groups were switched. After another 21 days of treatment had passed, another fMRI was done.

The fMRIs showed that parts of the brain had increased activity in the women who were taking
estrogen. The areas of increased activity included sections of the parietal and frontal lobes of the
brain. Activity in specific parts of these lobes increased when information (stimuli) was being
encoded or processed, when verbal information was being stored, and when information was
being recalled. The activity pattern seen during the encoding process was very similar to the
pattern seen in younger people.

While brain activity increased in women taking estrogen, they didn't actually perform better on
tasks. Researchers attributed this to the simplicity of the tasks used and recommended that
future studies be done using more complicated tasks.

Should further testing confirm the link between estrogen and memory, it would add to the
hormone's already impressive list of benefits, which include prevention of osteoporosis,
decreased risk of heart disease and colon cancer, and treatment of annoying menopause

52
symptoms like hot flashes and vaginal dryness. Several studies have linked estrogen to the
prevention of Alzheimer's disease and to the metabolism of cholesterol in the liver.

In addition to its benefits, remember that estrogen taken without progesterone seems to increase
the risk of endometrial cancer, and controversy remains over estrogen's role in breast cancer.

© Mediconsult.com 7/12/99

July 12, 1999

The Role Amyloids Play in Alzheimer's Disease
During the progression of Alzheimer's disease, plaques form in the brain, taking the place of
healthy, functional tissue. Researchers from the University of Washington report that they have
found a structure that contributes to the formation of these plaques, which are made of thin
strands (fibrils) of beta-amyloid protein.

Understanding how these protein fibrils are made will hopefully lead researchers to find ways to
block those formations, which could slow down the progression of Alzheimer's disease.

The newly found structure is located in proteoglycans, large molecules made by almost all the
cells in the body. In cartilage, proteogprovide stiffness and control the movement of fluid in the
cartilage. They are the reason why some cushioning fluid remains in joints, even after you've
been standing all day. In bone, they control what travels through the bone matrix. Unfortunately,
proteoglycans also play an important role in the origins of many diseases in addition to
Alzheimer's, including Down's syndrome, diabetes, cancer, arthritis, atherosclerosis, heart
disease, and AIDS.

In Alzheimer's and other disease processes involving amyloids, certain proteoglycans contribute
to the production of amyloids and also interfere with the body's ability to remove excess
accumulations. Once researchers decipher exactly how amyloids and amyloid fibrils are formed,
the next step would be to isolate substances and produce medications to interrupt the processes.

The National Institutes of Health (NIH) has recently funded two programs to investigate the role
amyloid plaque formation plays in Alzheimer's disease. The first one is looking specifically at the
mechanisms of plaque formation. What are the steps involved in their formation? The second
study will focus on prevention of the amyloid deposits and possible treatments for deposits
already present.

Healthwire April 16, 1999 )

1. Researchers Pinpoint Structure Within Proteoglycans Critical to Enhancement of Beta-Amyloid
Protein Fibril Formation That Occurs in Alzheimer's Disease.

2. ProteoTech Receives Funding For Two NIH Research Grants to Study the Cause, Prevention
and Treatment of Brain Amyloid Deposits Associated with Alzheimer's Disease

© Mediconsult.com 7/12/99

July 9, 1999
Brain Protein Interaction May Lead to Alzheimer's Disease
Researchers have reported findings suggesting that a certain protein interaction in the brain may
play a role in the development of Alzheimer's disease. Researchers at the Gladstone Institute of
Neurological Disease and the University of California-San Francisco studied the interaction of the

53
amyloid precursor protein (APP) and p53 proteins in mice to collect data; APP is associated with
Alzheimer's disease in its mutated form and p53 is known to be associated with cell death. It was
found that normal APP protected mice cells from the death-inducing effects of p53, but that the
mutated APP offered no such protection. Authors say it was not previously known that APP can
exert control over the cell death process and suggest that the failure of mutated APP to offer
protection in the brain may lead to Alzheimer's and other neurodegenerative brain diseases. The
findings are in the Proceedings of the National Academy of Sciences (1999;96:7547-7552).

© Mediconsult.com 07/09/99

July 5, 1999
Prevention of Mental Decline in Elderly May Be Possible
As we enter our senior years, it is inevitable that along with getting more wrinkles and gray hairs,
our mental processes also deteriorate. Right? Maybe not.

A study of nearly 6,000 senior citizens conducted by researchers at the University of California
Davis School of Medicine, have shown that those with advanced atherosclerosis (narrowing of
the blood vessels), peripheral vascular disease, or diabetes mellitus were at risk for a decrease in
cognitive function as they aged. This risk, however, was substantially magnified if the subjects
carried the apolipoprotein E4 (ApoE4) gene, a gene often linked with the development of
Alzheimer's disease. Interestingly, 70 percent of the participants showed no significant reduction
in cognitive function. This unaffected group had, in fact, two things in common: 1) they did not
express the ApoE4 gene, and 2) they showed few, if any, signs of diabetes or atherosclerosis.

Over the course of the study, subjects underwent a clinical assessment each year and answered
basic questions about their health history. They also had to perform simple cognitive tasks such
as recalling their birthdate, counting from one to five—both forwards and backwards and folding a
piece of paper in half. Those who scored the worst on the test were people who had both
atherosclerosis or diabetes and possessed the ApoE4 gene. These subjects were found be eight
times more likely to develop an impairment in cognitive ability than those who had low levels of
atherosclerosis and no ApoE4 predisposition. It was also shown that those with just the ApoE4
gene were three to four times as likely to have a loss in mental function than those who did have
the ApoE4. Finally, seniors with advanced atherosclerosis were three times as likely to have a
reduction in cognitive function as those who did not have atherosclerosis.

This study sheds some positive light on individuals entering their senior years, because it
suggests that the risk for developing cognitive impediments may be reduced, even in people with
a genetic predisposition, by preventing atherosclerosis and/or diabetes.

© 08/24/99 Mediconsult.com

June 28, 1999

Remember Your Estrogen
A common complaint as we age is a loss of short-term memory. Where did I leave my car keys?
Did I lock the front door? Researchers from Yale University recently released study findings
indicating that this problem in women may be partially due to a drop in estrogen level, which
occurs with menopause.

Forty-six women, with an average age of 50, were divided into two groups. One group received
estrogen for three weeks and the other a placebo. Then all the women received a functional
magnetic resonance imaging (fMRI) test while performing simple verbal and nonverbal memory

54
tasks. After a two-week break to allow the estrogen to dissipate from participants' systems, the
groups were switched. After another 21 days of treatment had passed, another fMRI was done.

The fMRIs showed that parts of the brain had increased activity in the women who were taking
estrogen. The areas of increased activity included sections of the parietal and frontal lobes of the
brain. Activity in specific parts of these lobes increased when information (stimuli) was being
encoded or processed, when verbal information was being stored, and when information was
being recalled. The activity pattern seen during the encoding process was very similar to the
pattern seen in younger people.

While brain activity increased in women taking estrogen, they didn't actually perform better on
tasks. Researchers attributed this to the simplicity of the tasks used and recommended that
future studies be done using more complicated tasks.

Should further testing confirm the link between estrogen and memory, it would add to the
hormone's already impressive list of benefits, which include prevention of osteoporosis,
decreased risk of heart disease and colon cancer, and treatment of annoying menopause
symptoms like hot flashes and vaginal dryness. Several studies have linked estrogen to the
prevention of Alzheimer's disease and to the metabolism of cholesterol in the liver.

In addition to its benefits, remember that estrogen taken without progesterone seems to increase
the risk of endometrial cancer, and controversy remains over estrogen's role in breast cancer.

© Mediconsult.com 06/28/99

June 16, 1999

Is There A Way Around the Blood Brain Barrier?
The blood brain barrier is both a blessing and a curse. Researchers at the Washington School of
Medicine in St. Louis believe they may have found a way to remove the curse.

As a blessing the blood brain barrier protects the brain from the many harmful substances
circulating in our blood. As a curse, it prevents necessary drugs from reaching brain tissue.

A protein called p-glycoprotein (Pgp), which prevents substances from entering the brain through
blood vessels, guards the blood brain barrier. This substance seems to work with another protein
MRP (multidrug-resistance associated protein) at a second brain barrier that lines the deep
cavities within the brain called the choroid plexus. The researchers are hoping the choroid plexus
will turn out to be a back door into the brain.

The normal function of the choroid plexus is to keep foreign substances from entering the
cerebrospinal fluid (CSF) that bathes the brain and spinal cord. This is the fluid that is removed in
a spinal tap. Researchers ahoping to figure out how to manipulate the protein that guards this
back door.

Research on how to cross the blood brain barrier has focused on blocking Pgp and hasn't been
very successful. Scientists at Washington University are wondering if there would be more
success if both proteins, Pgp and MRP, are blocked.

They will continue their research using animal models to try to discover exactly where and how
these two proteins guard the brain. Once this is known, the next step is to figure out how to use
them to help certain medications get into the brain.

If this method can be found, it could be used for the treatment of brain tumors, AIDS, depression,

55
and other diseases that hide behind the protective barriers that surround the brain.

© Mediconsult.com 06/16/99

June 16, 1999

It's the Vitamin E in Food that Prevents Heart Disease
If you're a woman who's passed through menopause, you're now more likely to develop heart
disease, suffer a stroke, and develop certain types of cancer. Researchers at the University of
Michigan have some advice for you. Increase your vitamin E, but do it with diet, not a pill.

Until this study, the emphasis was that postmenopausal women needed more vitamin E, so
physicians recommended they take a supplement. However, this study shows that the antioxidant
properties of vitamin E may not be effective unless you get it in food.

When low-density lipoproteins (LDL or 'bad' cholesterol) is oxidized, it can cause damage to your
blood vessels. The damaged areas are then prone to inflammation and plaque buildup. The more
plaque, the narrower and rougher the passageway becomes. All these conditions, which are
called atherosclerosis, increase your likelihood of developing a blockage in blood vessels, which
can lead to heart attack or stroke. Antioxidants work at the initial step, blocking the oxidation of
LDL.

Oxidation reactions are also linked to Alzheimer's disease, cancer, diabetes, cataracts,
rheumatoid arthritis, skin disorders, and hemochromatosis (iron overload syndrome).

Researchers at University of Michigan were looking for an explanation of a previous study

showing that women who got their vitamin E from foods, rather than supplements, had a lower
rate of cardiovascular disease (CVD). Their findings suggest that vitamin E in food blocks LDL
oxidization.

Women who got their vitamin E from supplements not only didn't get the beneficial antioxidant
effects, they actually had increased LDL oxidation, which increased their risk for cardiovascular
disease.

The vitamin E supplement dose in this study was low, taken via a multivitamin. Researchers
caution that the possibility that higher doses of vitamin E may be beneficial cannot be ruled out.
They also note that they can't say for sure that it was solely the vitamin E in foods that was
supplying all the antioxidant effects. However, they did rule out other known antioxidants—
Vitamin C, beta-carotene, and folic acid—as sources of antioxidant benefits in this study.

© Mediconsult.com 06/16/99

June 16, 1999

Why They Can't Find Their Way Home
The memory loss associated with Alzheimer's disease has led to disorientation, with people
suddenly finding themselves lost in their own home or neighborhood. Researchers at the
University of Rochester have found another explanation for this problem, which they call "motion
blindness".

Motion blindness occurs in a very specific part of the brain that deals with interpreting motion, and
it is different from the memory centers that are also affected by Alzheimer's disease.

56
When we move, whether it's walking, driving a car, or riding on a train, our changing environment
is taken in by our senses and interpreted in our brains. The researchers use the example of
driving through a snowstorm; our mind interprets that we are travelling forward through the snow,
not that we are still and the snow is traveling at 60 mph past us. Our surroundings provide
countless clues so we can determine where we are in relationship to our environment, and how
we are moving through that space.

As we age, we lose some of this motion detecting ability. When researchers brought a group of
people through the winding corridors of the medical center, 88 percent of the young people
correctly answered questions about the route they had taken. Seventy- three percent of the
healthy elderly people answered correctly, but only 32 percent of the people with Alzheimer's
disease could give the right answers.

In the early stages of Alzheimer's disease not all patients experience severe motion blindness,
which affects their sense of perception; some may exhibit extreme memory loss. Eventually, all
Alzheimer's patients will have both problems as the disease destroys both areas of the cerebral
cortex, but which aspect will show up first depends on which area is affected early on.

Researchers are planning to continue their study of this aspect of the disease with the hope of
being able to improve the quality of life for people with Alzheimer's disease and to further our
knowledge about the disease process.

© Mediconsult.com 06/16/99

May 7, 1999
Breakthrough Treatments Offer Hope for Victims of Neurological
Disorders
A U.S. pharmaceutical company recently received patents for new treatments that could help
people with Alzheimer's disease, Parkinson's disease, multiple sclerosis, ALS (Lou Gehrig's
Disease), and stroke—among others.

The patents are for treatments involving neuroimmunophilin ligands, a complex name for a group
of small molecules that can attach to other substances and, in animal subjects, have showed the
capacity to regenerate nerves that have been injured by accident or disease. Not only do they
have a positive effect on damaged nerves, but they show no effect on nerves that have not been
damaged.

This advancement could not only help those already stricken with these diseases, but also may
help prevent those diseases from occurring in the first place.

Neuroimmunophilin ligands are fairly new to the field of research. While they haven't yet been
proven to be effective or safe for use in humans, neuroimmunophilin ligands have the potential
for improving the lives of people who suffer from various chronic, degenerative, neurological
conditions.

A patent has also been granted for use of a group of enzymes called NAALADAse inhibitors,
which stop the excessive release of glutamate without interfering with normal glutamate levels.
Glutamate is a protein that acts as a neurotransmitter in the brain to excite neurons (nerve cells).
Too much glutamate has been linked to many chronic and acute degenerative nerve disorders
that with stroke, trauma, spinal cord injury, Parkinson's disease, and chronic pain. Experiments
with these inhibitors have also shown them to interfere with prostate cancer cell growth.

© Mediconsult.com 05/07/99

57
May 1, 1999
Researchers are Closing in on Alzheimer's
One theory of the cause of Alzheimer's disease is over production of certain proteins in the brain.
These proteins are believed to clump up and kill brain cells.

A new study from the University of Minnesota shows how these same proteins might contribute to
Alzheimer's disease in another way, by increasing production of oxygen radicals. These radicals
interfere with the ability of small blood vessels in the brain to deliver blood to brain cells. Without
an adequate blood supply, brain cells die.

By now, you've probably heard of antioxidants, a term used to describe the action of certain
vitamins such as Vitamin E. Antioxidants stop oxidation processes that damage blood vessels in
the brain. In preventing damage, they also help prevent Alzheimer's disease. In fact, a 1997 study
showed a slower progression of Alzheimer's disease in people treated with Vitamin E.

The research used lab mice, which were studied before they showed any sign of Alzheimer's.
Having oxygen radicals present seemed to cause a defect; the blood vessels couldn't dilate
normally. When activity in a section of the brain increases, the blood vessels supplying that area
should open up, or dilate, to provide the extra oxygen and nutrients needed. Oxygen radicals
prevent this dilation,causing the cells to starve and become weakened. The study also found that
if the mice's brains were bathed in an antioxidant, the radicals were rendered harmless.

Another study at Tel Aviv University, claims that simply having the Alzheimer's gene may
predispose you to poor recovery from a traumatic brain injury. Meanwhile researchers at
Allegheny University, Wayne State University and Johns Hopkins University are working on the
connection between bacterial and viral infections and Alzheimer's disease. Specifically, they are
studying the Chlamydia bacteria, a common cause of respiratory infections.

There are many new and exciting studies, research, and clinical trials currently going on for
Alzheimer's disease. Hopefully, someone will soon find the key to treating or preventing this
debilitating disease.

© Mediconsult.com 5/1/99

April 25, 1999

MRI Can Predict Alzheimer's Disease Before Symptoms Noticed
A recent report suggests that it may be possible to use magnetic resonance imaging (MRI) to
diagnose Alzheimer's disease before the onset of condition-related symptoms. Researchers at
New York University (NYU) used MRI to measure glucose metabolism in the brain and the
volume of various brain regions in elderly patients with progressive memory impairment to collect
data. It was found that the brains of memory-impaired patients appeared to show that Alzheimer's
disease progressed from shrinkage in the entorhinal cortex to atrophy of the hippocampus, and
finally to changes in the cerebral cortex that cause the dementia and extreme memory loss
characteristic of Alzheimer's. Authors say the stages of disease progression may occur over a
period of up to 30-40 years and that MRI could be used to help diagnose the disease before the
onset of clinical symptoms. The report was presented by NYU's Dr. Mony de Leon at the
Experimental Biology '99 conference in Washington, DC (April 21, 1999).

58
© Mediconsult.com 4/25/99

April 15, 1999

Study Suggests Smoking May Protect Against Parkinson's Disease
The more you smoke the less likely you are to develop Parkinson's disease. According to a study
done at the Henry Ford Health Centers in Detroit, people who smoke the most are the least likely
to develop this disease.

Researchers have acknowledged the link between nicotine and Parkinson's disease for years,
and it's been the focus of many studies-some of which have suggested that smoking protects
against developing Parkinson's and others concluding that smoking worsens the symptoms.

The latest evidence suggests that smoking less than 30 packs a year lowers the risk for
Parkinson's disease by 40 percent, while smoking more than 30 packs lowers the risk by 90
percent. Researchers believe that nicotine protects by altering some types of receptors and
chemical transmissions in the brain, avoiding the classic Parkinson's imbalance of the
neurotransmitter dopamine. Some studies suggest that nicotine only provides this benefit in
people with a certain gene. A study done at Salpetriere Hospital in Paris, France, correlated this
benefit with age: Nicotine appeared to protect against Parkinson's in a younger age group but
caused it in an older group.

A few studies indicate that if researchers could discover how nicotine's protective mechanism
works, it may have applications for Alzheimer's, schizophrenia, and addictions-all diseases which
involve disorders or imbalances of the brain's neurotransmitters or receptors.

While study conclusions vary, one thing the experts agree on is that more studies are needed to
understand the relationship between nicotine and Parkinson's disease.

Regardless of nicotine's role in preventing Parkinson's, smoking remains the leading cause of
other serious fatal diseases, including: cancers of the lung, cervix, bladder, pancreas, kidney,
larynx, esophagus and mouth; emphysema; hypertension; coronary artery disease; stroke; and
heart attack. None of the studies suggest that any potential protection smoking may offer against
Parkinson's disease outweighs the serious risk for developing any of these conditions.

© Mediconsult.com 4/15/99

April 11, 1999

Gene Mutations Associated with Alzheimer's Disease
Researchers have reported new findings concerning the increased risk of Alzheimer's disease
among people who inherit mutations in the presenilin genes. Note: an estimated 40% of people
with familial Alzheimer's disease have presenilin gene mutations. Researchers at Harvard
Medical School report that alterations made in the presenilin-1 gene in cultured laboratory cells
resulted in the inhibition of beta-amyloid precursor protein and in lower levels of amyloid-beta
protein, which forms the brain lesions found in Alzheimer's patients. Authors say the findings
suggest that presenilin may be the long-sought enzyme that is responsible for the overproduction
of beta-amyloid in Alzheimer's patients. The findings are in the journal Nature (1999;398:466-
467).

© Mediconsult.com 4/11/99

59
April 7, 1999
Effects of Constant Caregiving on Immune System Function
Researchers at the University of California, San Diego, have found that the stress of caring for a
sick loved one can reduce a person's own ability to fight illness. The researchers measured
immune system markers in the blood of 41 elderly men and women caring for spouses suffering
from Alzheimer's disease and found that those who rarely got a break from caregiving had 60%
fewer active CD8 T cells and significantly fewer active CD4 T cells compared to less-stressed
caregivers. (T cells are white blood cells that help rid the body of invading pathogens.) Vulnerable
caregivers also reported that their illnesses lasted three times longer than the non-vulnerable
caregivers. Researchers further suggest that elevated levels of the stress hormone epinephrine
may inhibit levels of active immune system cells. The findings are in the journal Psychosomatic
Medicine (1999;61:168-174).

© Mediconsult.com 4/7/99

March 26, 1999

'Motion blindness' may cause Alzheimer's Patients to Lose Their Way
A recent report suggests that vision problems may have more to do with Alzheimer's disease
patients getting lost than confusion or memory loss. Researchers studied six healthy young
people, 12 healthy elderly people, and 11 patients with Alzheimer's disease to collect data;
participants were tested on their recall of a traveled route and were asked to determine the
direction of movement in several computer simulations. It was found that Alzheimer's patients
were significantly less likely than members of the other groups to be able to correctly answer
questions about a route they had traveled and were found to have twice as much difficulty in
determining direction of travel on computer simulations, compared to members of the other
groups. Authors suggest that damage to the parieto-occipital cortex brain region in Alzheimer's
patients may lead to "motion blindness," a condition in which the visual analysis of optic flow and
spatial orientation are impaired. The report is in the journal Neurology (1999;52:958-965).

© Mediconsult.com 3/26/99

March 19, 1999

Blood Protein Linked to Slowing Alzheimer's Disease
Researchers have reported findings that suggest an association between the blood protein apoE
and a slowing of the development of Alzheimer's disease. Researchers at the Washington
University School of Medicine in St. Louis, Missouri, studied the effects of apoE on the
development of Alzheimer's-related factors in mice to collect data. It was found that mice
genetically engineered to produce human amyloid-beta peptide, which forms plaques in the
brains of Alzheimer's patients, developed plaques by the age of nine months, but that those mice
who were also engineered to produce human apoE did not develop the plaques by the same age.
Authors suggest that apoE may remove amyloid from plaques and note that the increased risk of
Alzheimer's previously found to be associated with one form of apoE (apoE-4) may be due to a
decreased ability of that form to remove amyloid, compared to other variants. The findings are in
the "Journal of Clinical Investigation" (March 15, 1999).

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March 19, 1999
Mild Memory Loss is Not an Indicator of Early Alzheimer's Disease
A recent study sought to examine distinctions between age-related mild cognitive impairment
(MCI) and the early stages of Alzheimer's disease. Researchers at the U.S. National Institute on
Aging in Bethesda, Maryland, studied more than 400 people over a period of 10 years to collect
data. The study found that MCI and early-stage Alzheimer's disease could be clearly
differentiated using a battery of mental status tests. The report says that patients suffering from
MCI have specific memory problem, but do not exhibit problems in other cognitive domains, such
as language, judgement, and a variety of communication abilities, that are characteristic of
Alzheimer's disease. Authors further note that those patients suffering from MCI appear to be at
increased risk of developing Alzheimer's disease, compared to healthy people over the age of 65.
The report is in the "Archives of Neurology" (1999;56:303-308).

© Mediconsult.com 3/19/99

February 26, 1999

Alzheimer's-related Protein Linked to Learning Disabilities
Recent study has found that mice genetically engineered to produce a protein associated with
Alzheimer's disease show evidence of severe learning disabilities. Researchers at the University
of Minnesota Medical School in Minneapolis engineered mice to produce a mutant version of the
amyloid precursor protein (APP), which is found in Alzheimer's- related plaques in the brain in
humans. The study found, as the mice developed APP brain plaques, that they began to poorly
on learning and memory tasks, which researchers say appeared to be primarily based in
impairments to forming nerve cell connections in response to cell activation. Authors say the
findings suggest that new forms of treatment that concentrate on restoring proper nerve function,
instead of replacing dead brain cells, could be used to treat Alzheimer's disease. The study is in
the journal Nature Neuroscience (1999;2:271-276).

© Mediconsult.com 2/26/99

February 26, 1999

Exercise May Stimulate New Cell Growth in Brain
A new report suggests that vigorous exercise may stimulate the development of new cells in the
hippocampus, a brain region known to play a key role in learning. Researchers at the University
of Illinois in Urbana say they used fluorescent staining techniques to locate recently-formed cells
in the hippocampi of mice that lived in various environments and performed specific tasks. It was
found that those mice that engaged in voluntary exercise on a running wheel showed about
double the level of new cell proliferation, compared to controls. Authors say the findings also
suggest that exercise may help to prolong the life of already-established cells in the
hippocampus. The findings are in the journal Nature Neuroscience (1999;2:203-205).

© Mediconsult.com 2/26/99

February 26, 1999

Interesting Environment Linked to Changes in Brain 's Memory System

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A new report concludes that environmental complexity appears to increase the production of
adult-generated hippocampal neurons in mice. Researchers at Princeton University and Rutgers
University studied the hippocampal regions of mice exposed to living spaces filled with
interesting, varied objects and stimuli to collect data. It was found that mice exposed to the
complex/stimulating environment showed increased production rates of neurons in the
hippocampus, compared to mice not exposed to such an environment. Authors say the findings
suggest that learning about space and environment has growth-inducing effects on hippocampal
neurons and speculate that the hippocampus may have developed to aid the cerebral cortex "by
adding neurons that can deal with new information while deleting those that encode obsolete
information." The findings are in the journal Nature Neuroscience (1999;2:260-265).

© Mediconsult.com 2/26/99

February 26, 1999

Study Links Common Herbal Supplements With Infertility
A new report suggests that high doses of several popular over-the- counter herbal supplements
could impair fertility. Researchers at Loma Linda University School of Medicine in California
studied the effects of high doses of St. John's Wort, echinacea, gingko, and palmetto on the
ability of sperm to penetrate hamster eggs in a laboratory setting to collect data. It was found that
high doses of St. John's Wort prevented sperm from penetrating eggs, while echinacea and
gingko impaired such penetration; palmetto did not appear to effect penetration. Authors further
note that sperm exposed to St. John's Wort for more than a week appeared to be damaged and
say that further study is being planned to evaluate the actual effects of the herbs on fertility when
taken by humans. Notes: St. John's Wort is marketed for treating depression and anxiety, gingko
for improving memory and helping patients with Alzheimer's disease, palmetto for easing prostate
problems, and echinacea for boosting the immune system. The report is in the journal Fertility
and Sterility (February 22, 1999).

© Mediconsult.com 2/26/99

February 19, 1999

Cognitive Decline Associated with Serious Head Injury
A new study concludes that serious head injury may be associated with an increased risk of
Alzheimer's disease and other age-related dementia in elderly patients. Researchers at the
University of Oulu in Finland studied 588 Finns aged 70 and older, some of whom had suffered
head injuries, over a 2.5-year period to collect data. The study found that those participants who
showed the highest levels of decline in cognitive ability over the study period were about four-
times as likely as others to have suffered a head injury and that, overall, about 20% of all head
injuries were associated with later decline in mental ability. Authors note that minor head injuries
did not appear to be associated with declines in cognitive function and that the findings suggest
that both head injury and Alzheimer's disease may trigger neurological decline in similar ways.
The study is in the journal Neurology (1999;52:557-562).

© Mediconsult.com 2/19/99

February 8, 1999
Dental Mercury Does Not Cause Alzheimer's Disease

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A recent study concludes that dental amalgam (silver dental fillings) and its mercury component
do not appear to play roles in the development of Alzheimer's disease. Note: previous research
has found imbalances of some metal elements, including mercury, in patients with Alzheimer's
disease. Researchers at the University of Kentucky at Lexington studied 68 Alzheimer's patients
and 33 control subjects to collect data; the dental histories of all patients were examined, as was
information on their non-dental exposure to mercury. The study found no evidence of a link
between dental amalgam and increased risk of Alzheimer's. Authors say the study is the
thorough clinical pathological correlative study of humans to show that dental amalgam is not a
neurotoxic factor in the development of Alzheimer's. The study is in The Journal of The American
Dental Association (February, 1999).

© Mediconsult.com 2/8/99

January 30, 1999

Alzheimer's Gene Associated With Poor Brain Injury Recovery
A new report suggests that a gene previously linked to an increased risk of Alzheimer's disease
may also be associated with poor recovery from traumatic brain injury. Researchers at Tel Aviv
University, Israel, studied 69 patients with severe brain injuries to collect data. It was found that
those patients who expressed the apolipoprotein E-4 (Apo E-4) gene were five-times more likely
to spend seven or more days unconscious as a result of their brain injury than those without the
gene; six months after brain injury, those patients with the gene were significantly more likely to
be suffering form complications such as speech problems, behavioral abnormalities or difficulty in
swallowing than those without the gene. Authors say that, overall, those with Apo E-4 were about
14-times more likely than others to have a less-than-optimal outcome following head injury and
suggest that the findings could indicate a possible means of tailoring treatment to each patient
following trabrain injury. The findings are in the journal Neurology (1999;52:244-248).

© Mediconsult.com 1/30/99

January 14, 1999

Rate of Iatrogenic Disease-Related ICU Admissions Remains
Unchanged
A new report says the percentage of hospital intensive care unit (ICU) admissions due to
prescription drug side-effects and complications from medical procedures has remained
unchanged since about 1980. Note: illness from prescription drug side-effects and complications
from medical procedures are collectively known as "iatrogenic disease." Researchers at General
Hospital in Compiegne, France, examined the rate of iatrogenic disease-related ICU admissions
over the course of a year at the hospital and compared the findings from a similar study from
1980 to collect data. It was found that about 11% of ICU admissions were related to iatrogenic
disease in the current study, compared to 12.6% in the 1980 study. The report notes that 41 of
the 68 iatrogenic disease- related admissions in the current study were linked to adverse drug
effects, 15 to surgical complications, and 12 to complications from other medical procedures; 22
of the admissions were attributed to negligence on the part of healthcare staff The report is in the
Archives of Internal Medicine (1999;159:71-78).

© Mediconsult.com 1/14/99

January 8, 1999
New Screening Guidelines for High Risk Heart Disease

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The American Heart Association has issued new guidelines on the screening of some patients for
elevated homocysteine levels. Note: homocysteine is an amino acid that is used both in the
production and maintenance of body tissues; elevated homocysteine levels can lead to the
clumping of blood platelets, which can increase the risk of heart attack and stroke. The AHA
science advisory says more than one in three people with heart disease experience high levels of
homocysteine and that high-risk patients, including those with a personal or family history of heart
disease be screened for high levels of the amino acid. Elevated homocysteine levels, which are
generally correctable through dietary changes, have also been linked to Alzheimer's disease,
chronic fatigue syndrome and rheumatoid arthritis. The AHA science advisory is in the journal
Circulation (January 5, 1999).

© Mediconsult.com 1/8/99

January 7, 1999
Rate of Brain Tissue Loss No Different in the Elderly
A recent report concludes that, despite long-held beliefs to the contrary, the natural loss of brain
tissue over time does not accelerate during the last decades of life. Researchers at the Oregon
Health Sciences University in Portland used magnetic resonance imaging (MRI) to study the
volume of brain regions in 46 healthy volunteers, ages 65-95, to collect data. It was found that
while the volumes of certain brain regions did decrease over time, the rate of such decreases
remained relatively constant, even in the oldest patients. Authors say previous studies that
suggested an accelera tion in brain tissue loss with age may have included patients in the earliest
stages of diseases characterized by brain-tissue damage-related dementia, while the current
study excluded all patients who showed signs of such conditions. The report is in the journal
Neurology(1998;51:1-7).

© Mediconsult.com 1/7/99

December 22, 1998

Drug Treatment of Dementia Symptoms
A new report concludes that Janssen Pharmaceutica, Inc.'s Risperdal(r) (risperidone) appears to
be effective in reducing psychotic symptoms associated with dementia, schizophrenia and other
forms of psychosis in elderly patients. Researchers randomized 330 Alzheimer's disease
patients, with an average age of 82.7 years, to receive either a placebo or 0.96 mg/day of
Risperdal daily for one year to collect data. It was found that patients treated with Risperdal
showed significant reduction in both psychosis and aggressive behaviours, compared to placebo
recipients. Authors further note that only one recipient of the drug developed tardive dyskinesia, a
condition characterized by involuntary movements and uncontrolled facial grimacing that is a
common side-effect of other anti-psychotic medications. The report was presented at the 37th
annual meeting of the American College of Neuropsychopharmacology in San Juan, Puerto Rico
(December 16, 1998).

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