By Charles S. Yanofsky,
M.D.
©2003
PA Neurological Associates, LTD
717-774-2202
Charles S. Yanofsky, M.D.,
F.A.A.N
Jon L. Vickery, M.D., F.A.A.N.
Albert W. Heck, M.D
Francis J. Janton, III, M.D.
Liana Laza, M.D.
Lee B. Peterlin, D.O.
David Finkelstein, M.D.
Contents:
Other
issues and their treatments
Marginally
Effective Strategies
The
Death of Alzheimer Disease (A Cure)
When to the sessions of sweet silent thought
I summon up remembrance of things past,
I sigh the lack of many a thing I sought,
And with old woes new wail my dear time’s waste:
Then can I drown an eye, unused to flow,
For precious friends hid in death’s dateless night,
And weep afresh love’s long since cancell’d
woe,
And moan the expense of many a vanish’d
sight:
Then can I grieve at grievances foregone,
And heavily from woe to woe tell o’er
The sad account of fore-bemoaned moan,
Which I new pay as if not paid before,
But if the
while I think on thee, dear friend,
All losses are
restored and sorrows end.
-W. Shakespeare Sonnet XXX
A few years ago the title of
this article was an oxymoron. There was no viable treatment for an estimated
current 4 million Americans with Alzheimer’s disease. Over the last few years
we’ve had advances that have made treatments possible, though, alas, there is
no cure for the disease and although current therapies are promising, none has
been found that slows down the basic progression of the disease.
It’s hard to believe that
Alzheimer’s disease is known to physicians for less than a century. Over that time, and until recent years,
neuropathology defined the disease. If we could only explain microscopic
findings, then, we’d have an idea of what to do about it. The largest emphasis
in training neurologists went to drilling into their impressionable minds, four
or five neuropathological features. It starts and is
best seen in the hippocampus
of the brain. There are changes present in most aging brains but increased in
Alzheimer’s brains, cerebral atrophy, neuronal loss, senile
plaques, neurofibrillary tangles, granulo-vacuolar
degeneration. For decades in the
twentieth century these changes were drummed into the heads of medical
students, neurology residents and other trainees though never to be seen in the
many patients they would treat, except in the event of death and autopsy or
even much less probable, on biopsy of a living brain, something very rarely
done as it requires invasive neurosurgery. No one knew for certain why these
dramatically visible changes appeared, but it was hoped that we might
understand them and then find a way to prevent or reverse these changes.
The other side of the coin
was the clinical presentation. Most of
the time this would be in an elderly individual, more often a woman than a man,
easier to recognize in a person with less sophistication (e.g. the “Nun Study”), of lower socioeconomic class
and with less education. Most typically Alzheimer’s presents with memory loss,
especially loss in what is termed recent memory. It then progresses to affect
eventually all mental endeavors, and literally devours the personality over
time. The clinical course, noticed first by spouses, children and other family
members, is insidiously slow and it is to be expected that the sufferer will
end up first in adult day care or require extra care at home, and inevitably in
a skilled nursing facility often for a long time.
Alzheimer’s like other
diseases has many faces. Just some of the phenomenology of a disease includes
neuropathology, animal models. But you can study clinical presentation and
course of the disease, social and economic costs, epidemiology. You can look at
risk factors for the disease – for Alzheimer’s the chief risk is aging. You may
study radiological changes, a
fascinating area in and of itself because it’s possible to make the diagnosis
with the right tools, imaging tests such as PET that show the metabolic
activity of various brain regions, well before the disease becomes clinically
manifest. Also available for study are
diagnostic findings and pitfalls and what is called differential diagnosis,
other diseases that mimic this disease, genetics, medical interventions that
have empirically been found to help sufferers and families, those that don’t,
the clinical handling of the disease, and physiologic and electrical changes
brought about by the disease as on EEG, MEG,
chemical changes in the brain, drug and non-drug treatments and effects.
Still, you haven’t run out of ways to
look at a disease.
Over the years as doctors
deal with a disease, some of them treating patients or doing research, we build
a body of knowledge and develop strategies for treatment. We know now
neuropathology was over-rated, though we had microscopes and it was something
one could see to help understand the disease.
And physician’s knowledge is always determined by the tools they use to
study their subject. This wasn’t true 20
or thirty years ago, but the microscope, is no longer a sexy way to study a
disease. Not very much information was developed until recently, about how microscopic
changes actually developed and what made them occur.
Nowadays we mostly see
disease through the lens of chemistry.
Today’s research is driven by pharmaceutical houses mostly, much less by
universities and the government. Drug companies want desperately to find and
sell what will be useful. They end up hiring doctors who work for medical
schools and those in private practice too, for empirical studies designed to
show that a certain compound or protein typically works or at least can be made
to seem to work. These companies often bet hundreds of millions of dollars on a
drug or treatment and hire cadres of eminent scientists and statisticians to
prove they’re right. It’s a competitive world. Other companies may have the
same idea and their own product also trying to be first or at least better than
another product in that same class. They are in a race to find useful
compounds, first to treat the cognitive decline of the disease, but eventually
to prevent it.
Current therapies for Alzheimer
disease relate to the transmitter Acetylcholine (Ach). This is one of the first neurotransmitters
known. A neurotransmitter is a chemical signal allowing neurons (nerve cells)
to communicate. Neurons communicate with fellow neurons though a synapse, a
tiny microscopic space. They signal the
next cell by secreting a neurotransmitter, affecting the next neuron by fitting
into a receptor on the surface of the cell.
More is known about ACh than any other transmitter.
One reason is that ACh is the signal that nerves use to make muscles contract.
When you need a voluntary muscle to contract, the command comes through the
nerve going to the muscle. Then comes the synapse between nerve and muscle, the
neuromuscular junction. At the right time ACh streams
across the synapse, fits into the receptor on the membrane of the muscle, and
signals the muscle to contract.
The same holds for neurons in
the brain. ACh
is a simple chemical which is made, as
biological chemicals are, by enzymes. The enzyme forming ACh is CAT for Choline- acetyl transferase. But when a neuron secretes a chemical
transmitter there has to be some means to turn it off. Otherwise the signal
would keep affecting the receptor and it would be impossible to signal again,
or the effects would continue to be felt. In general signals must have an acute
onset and offset, otherwise they can’t function to send a message. Another
enzyme quickly degrades Ach, Acetylcholine esterase or AChE.
AChE breaks
down Acetylcholine (ACh).
When you look at a chemical
like this you see two parts to the molecule. The most important is the business
end. For a neurotransmitter like ACh, the business end of the molecule is rather simple,
N-CH3. The rest of the molecule is a
sort of “carrier” but it is a characteristic of just about all
neurotransmitters, that they are simple molecules. Not only are they simple.
They are somewhat universal. Somewhere
early on in evolution, certain molecules that were easy to assemble, became
messengers. ACh is a perfect example. It is not only a messenger in humans, but in
almost all animals and here we are talking about not just mammals but distantly
related animals on the evolutionary bush, insects and other arthropods. In fact, some neurotransmitters such as Serotonin function as messengers not
only for animals but for plants.
Over wide stretches of
Alzheimer brains it’s been known for a very long time that there is a reduced amount
of all of these actors, ACh, AChE,
CAT. So we have another very important
way to look at Alzheimer disease, defining Alzheimer chemistry. Here is a case where scientists had
identified a change and to some extent it may be possible to reverse that change. Bear in mind this has not been the case with
some of the microscopic changes in the disease.
We don’t have an easy way to
prevent the formation of senile plaques or neurofibrillary
tangles etc. But here, we know that
there is a deficiency of ACh and there may be some
easy way to replace it – very exciting stuff.
The nucleus Basalis of Meynart lies at the
base of the brain and distributes signals to the upper cortex especially layers
I and II the outermost cells of the brain. This is all over the cerebral
cortex. That nucleus is cholinergic, meaning that the transmitter it uses is ACh. Researchers have found that reductions of ACh, AChE, CAT and the chemical
proteins that are receptors for ACh are all
correlated with the degree of dementia in Alzheimer disease. This adds fuel to the fire for the desire to
increase ACh in Alzheimer patients.
Parkinson disease it was
discovered decades ago was a similar problem.
There was degeneration in an area called the substantia
nigra or black substance. This part of the brain used
chiefly Dopamine as a transmitter and distributed it to other areas of the
brain, the basal ganglia. The most
effective treatments for Parkinson disease replace the deficient dopamine or
use drugs that mimic Dopamine. For
Alzheimer’s disease neurologists dreamed of doing the same, only for ACh.
Some medicines block the
effects of ACh. Included are many antihistamines,
psychiatric drugs, older antidepressants and antipsychotics,
drugs that block bladder spasm, dizziness drugs, medicines used in anesthesia,
some drugs used to treat Parkinson’s disease.
This means anticholinergics, as they are
called, are quite common and most of them do get into the brain. They can cause loss of memory function or
worse, confusion, even florid delirium and hallucinations. If a person is
overdosed with these medicines and has mental effects, they may have some
similarities with patients with Alzheimer disease but they fail to reproduce
the phenomena we see with Alzheimer’s.
On the other hand, older patients who certainly have some of the changes
of Alzheimer disease, and Alzheimer patients, are very sensitive to the mental
effects of these medications.
Atropine is an interesting
example. It is used in anesthesia. Used alone, Atropine only minimally
decreases pain or puts a person to sleep. A person under the influence of Atropine
will experience pain and may suffer but they won’t remember it. That brings up one of the interesting
questions in experimental neurology. What if a person having an operation
experiences everything, including all pain, but can’t later recall it. Is that
a legitimate form of “anesthesia”? To an extent it is. Much of the psychic pain
after a procedure occurs when the procedure is remembered again, when it
somehow becomes part of you, enters your memory stores. So anesthesia that
merely blocks registration of experience, does something positive.
Structure of Atropine.
Atropine is the classic "Tropine alkaloid"
a plant substance containing N-CH3 structure mimicking the business end of
Acetylcholine
According to legend,
Odysseus’s men were poisoned by the witch Circe with Jimsonweed[i].
Her spell caused his men to forget about their home. But Odysseus found an
antidote which may have been Galantamine from Common
snowdrop (Galanthus nivalis,
thus freeing his men. Relatives of
atropine are belladonna alkaloids which are named for their property of
dilating the pupil of the eye. Beautiful
young women have large pupils. As we age the pupil of the eye is reduced in
size.
On
one level, the memory disturbance of Alzheimer disease may be thought of as a
deficiency in acetylcholine. We could do a lot by finding some means of
increasing that chemical. In Parkinson’s disease, myasthenia gravis and other
conditions, we are working with the same kind of model, trying to replace a
deficient neurotransmitter. When you do replace the deficient transmitter, that
will not cure the disease, only help ameliorate some problems. That’s because there are structural changes
in most diseases that simple replacement of a transmitter does not address. In
any event this would be expected to help the Alzheimer patient to some extent.
That is our experience with the Cholinergic drugs.
For many years we had no
cholinergic drugs that could be used to Alzheimer disease. We have older drugs that are designed to
increase ACh.
The problem was that they got into the blood but couldn’t penetrate the
brain, unable to cross the blood brain barrier. The BBB protects the brain by
keeping out many toxic substances. There were medicines ending with “stigmine”, physostigmine, pyridostigmine, neostigmine. All
of these were used to treat myasthenia gravis which is a muscle disease in
which ACh loses its effect due to an immune attack on
the Ach receptor and also in anesthesia where neuromuscular blockers are used
and need to be reversed. Physostigmine could get into the brain but could not be
given by mouth and had an extremely short effect. We had no way of administering
these medicines efficiently over long periods, by mouth. In desperation neurosurgeons tried putting
tubes into the ventricles of the brain administering some of these medicines
but without prolonged beneficial effect.
|
characteristic |
Tacrine Cognex |
Donepzil Aricept |
Rivastigmine (Exelon) |
Galantamine (Reminyl) |
|
Dose/D |
4 |
1 |
2 |
2 |
|
Max dose |
160 mg |
10 mg |
12 mg |
24 mg |
|
Food? |
no |
no |
yes |
Yes |
|
D:D interactions? |
yes |
yes |
None known |
Yes, some |
|
Initial dose |
40 mg |
5 mg |
3 mg |
8 mg |
|
Introduced |
1993 |
1996 |
2000 |
2001 |
|
BUChE effect? |
Yes |
No |
Yes |
No |
However, in the 1990’s four new
drugs were released for the treatment of Alzheimer disease. All four agents
work the same way. They block the degradation of ACh
by temporarily affecting AChE. By the way, irreversible AChE blocking drugs also
exist. These are the highly toxic “nerve gases” such as Sarin
and organophosphates used mostly as insecticides. Very potent chemicals that
poison the AChE enzyme permanently can be
lethal. For these agents Atropine helps
as a partial antidote. For persons so poisoned and this has now become a central
fear in Bioterrorism, we administer huge doses of
atropine repeatedly. Some important
features of reversible type AChE blockers used to
treat Alzheimer’s are listed in the table above.
The very first was Tacrine or Cognex © rarely used
anymore. Tacrine was found to cause significant liver
toxicity sometimes, but it was effective and generally safe when blood work was
used to monitor the liver. It brought about a positive effect on behavior,
memory, cognition and it was shown to delay nursing home intervention. In clinical experience the effect was
variable as we’ve found with all these agents. A very few patients for some
reason, seemed to improve quite noticeably, performing tasks that they were
unable to do before and showing more spontaneity and energy. For the vast majority, improvement was
disappointingly modest. This has been our experience with all of the four
medicines at this point.
The other three (newer) drugs
listed above, do not cause liver toxicity and are chemically distinct from Tacrine. They can be
administered as little as once or twice a day so that considering the dangers
there is no need to use tacrine anymore, or at least
no reason to start it in new patients.
The next released agent was Aricept© (donepezil) which is a
good drug easy to use and with a half life of about 72 hours (measure of length
of time it remains in the blood before being cleared) so that Aricept can conveniently be given on a once a day basis.
Dose escalation is easy too. Many patients can be started and left with 5 mg.
once a day. Some relatively few improve a bit more on 10 mg. and the cost is
about the same so that most physicians find themselves using 10 for the average
patient who can tolerate it.
The other two yet newer agents
are somewhat more cumbersome to use. These are Exelon
© (Rivastigmine) and Reminyl
©, galantamine. Galantamine
is that naturally occurring plant alkaloid that Odysseus may have used from the
common snowdrop plant. Extensive clinical studies have been done with all these
agents. Exelon though having some other side effects,
affects another enzyme which breaks down acetylcholine, butyrylcholinesterase
(BChE). As Alzheimer’s progresses and the amount of AChE diminishes, the importance of BChE
increases and blocking this enzyme may become more important. This is a
theoretical consideration and we don’t really know the practical consequences.
Nevertheless the BChE blocking effect may enhance Exelon’s effect. The
problem is that BChE also exists outside the brain
and some of the adverse side effects may also be increased.
The side effects of all the
Anti-Esterase drugs are Cholinergic and make eminent sense and are easy to
remember as long as you know the effects of acetylcholine. The antiesterase drugs block the degradation of ACh and thus prolong its effect. It’s worthwhile taking a
look at some of the major functions of this powerful neurotransmitter. You will
find a further description in the endnotes below[ii].
The doses of Aricept, Exelon and Reminyl should be increased very slowly, now more often
than every 2 to 4 weeks. If the doses are raised too quickly and this is
especially true for Exelon, more uncomfortable muscarinic effects are likely to limit the use of what may
be effective medication. Started and increased too quickly, patients and
families may not tolerate the drugs that given a little patience can turn out
to be useful and tolerable. Typical doses are given in the table above.
These drugs work, but their
effect is often disappointingly modest. Effects are along three parameters
designated ABC, Activities of Daily Living, Behavior, and Cognition.
Alzheimer patients started on
anti-esterase medicine can expect improvements along all of the above three
parameters though variably and modestly. Some persons don’t seem to improve at
all but their rate of decline is lessened by the drug. For instance the area of
activities of daily living includes many issues ranging from buttoning one’s
own shirt, to picking out clothes to wear, being cognizant about changing
clothes, such issues as appropriate attire, all the way to being able to tie
one’s tie or shoelace and in poorly functioning individuals shaving, hygiene,
toileting etc. When a person is letting his personal hygiene go any improvement
may count as a blessing for those supervising him.
Behaviors fall into the same
category. Commonly there is a disinhibition ranging
from inappropriate racial or sexual joking and insulting behavior, to paranoia,
and depression also wandering and disorientation particularly at night are
problems. Modest improvements in any of these areas can be very helpful. Again,
medicines have been shown to slow the inevitable decline in this area.
Cognition declines go hand in hand with behavioral manifestations. Behavior
largely changes as a function of lost mental power. Disorientation and absent
recent memory especially contribute to behavior changes.
|
Brand Name |
Generic Name |
Comment |
|
Anti-Depressants: |
|
|
|
Elavil, Endep |
amitriptylene |
Given at bedtime, aid sleep |
|
Tofranil |
imipramine |
ditto |
|
Pamelor |
nortriptylene |
|
|
Anti Psychotics and
anti-emetics: |
|
|
|
Thorazine |
chorpromazine |
May be necessary to curb
psychosis |
|
Mellaril |
thioridazine |
ditto |
|
Phenergan |
promethazine |
For nausea and vomiting |
|
Compazine |
prochlorperazine |
ditto |
|
For urinary urgency and
bowel anti-spasmotics. |
|
|
|
Detrol |
tolteradine |
Urine urgency |
|
Bentyl |
dicyclomine |
Irritable bowel |
|
Pro-bantine |
propantheline |
Irritable bowel |
|
Ditropan |
oxybutynin |
Urine urgency |
|
Antihistamines: |
|
|
|
Benedryl |
diphenhydramine |
Helps for sleep |
|
Antivert |
meclizine |
For dizziness |
|
Chlor-trimaton and other |
chlorpheniramine |
For allergy |
Here is a table of some
commonly used drugs that in some ways have effects opposite to the Anti-esterase
drugs discussed (anti-muscarinics). They are
anti-cholinergic and may have mental effects in the elderly and those patients
with Alzheimer’s disease. If you see that your family member is taking any of
these agents, I’d suggest it is not a medical emergency. I mention this because
some families having a little knowledge of this nature and getting wind that
their loved ones are on such medicine suddenly insist they know what’s best,
begin to stamp their feet. Formerly reasonable intelligent people become irate
at times. You might bring it to the
attention of your doctor and he or she may have good reason to use one of these
drugs, but may consider an alternative.
All of the Alzheimer drugs have
proven to the satisfaction of the FDA that they either improve patient
functioning or slow cognitive decline. The studies have been released and show
incontrovertible effects. In order to prove this various more sensitive scales
have had to be derived. The popular and rapidly performed Folstein
Mini Mental Status test in almost universal use is a 30 point scale that
emphasizes language and recent memory functions. Typically it’s difficult to
appreciate a change on this scale. Most patients are already in the mild range
of disability scoring about 18-26 by the time they commence treatment. Evidence
for slowing of decline is easily demonstrable on such measures as the 70 point
ADAS-Cog scale. On this scale higher scores indicate greater impairment, mild to
moderate impairment is in the range of 15-25 and untreated Alzheimer patients
typically increase by 6-12 points per year. Another scale, the CIBIC-plus, is
more sensitive to change is a clinician’s interview-based impression and ranges
from a score of 1 showing marked improvement, to 4, no change, to 7 marked
worsening and so is sensitive to change. Typically over a period of 6 months or
so treated patients may not decline by very much whereas by about 6 months the
ADAS-cog might show a spread of an average of 5 or 6 points between treated and
untreated groups. As a clinician, I can appreciate as patients return to the
office, mostly a slower rate of decline than I’m used to with Alzheimer
patients. If I ask a patient and family to return in 6 months, very often the
caretaker will not appreciate any change over that period. In the old days
before these medicines a noticeable decline would almost always be palpable and
for that we have to be thankful.
Some few patients seem to
improve more than others. We don’t know why and also some folks notice that
whereas the patient may have been apathetic and unreactive
he or she might seem to be agitated soon after starting on drug. This is most
often temporary and acute and we can get around it either by using a mild
sedative or slowing down the upward titration of medicine. One very remarkable
result that has been found pretty universally is a delay of entry into skilled
care nursing facilities among treated patients. That is good for everybody as
very often some of the more rapid declines occur either with hospitalization or
nursing home placement. Cognitively
impaired patients have trouble dealing with a change in their surroundings and
of course the quality of life often suffers after placement. Also placement is
a sensitive indicator again of profound impairment. Financial considerations
are important too.
The anti-esterases
are all approved for the mild to moderate Alzheimer patient, those with
mini-mental scores of about 10-26. They are not approved for Minimal Cognitive
impairment, a disorder among the elderly characterized by recent memory loss
alone and mini-mental scores in the range of 27-30 approximately and the risk
of developing other signs of Alzheimer’s disease in the range of 10% per year. Also
their use in advanced cases is problematical. The main advantage of these
compounds is the delay of deterioration, for example, delaying nursing home
placement and maintenance of cognitive function over a longer period of time.
A new compound memantine (Namenda ©) has
recently been approved for moderate to severe disease. It is an NMDA
antagonist. NMDA receptors are a subset of glutamate receptors related to excitotoxic effects implicated in neuronal destruction. This
compound has been tested alone and with Aricept and
may bring about modest gains. Namenda is the first of
a new class of compounds (non-ACHe-I’s) released in
the
Treatment of ancillary
symptoms of Alzheimer disease has improved as well. Techniques have evolved to
treat depression, sleeplessness, agitation, paranoia, Parkinsonian
symptoms and seizures which are often co-morbidities. First as regards
personality there is some literature to the contrary, but I’m impressed that
true personality changes for the average patient occur little, if at all, until
late in the disease. In fact if personality changes are most prominent, then
one ought to consider other entities which affect personality and the frontal
lobes primarily such as fronto-temporal dementia, or cortico-basal ganglionic
degeneration. Late in Alzheimer’s
there can be a stage rarely of delirium and agitation, most often engendered
either by medication or intercurrent infection or
illness. It is not until very late that mobility is affected and the subject
reaches a bed-ridden state and unresponsiveness.
More often Alzheimer’s
perpetuates and magnifies previous personality quirks. A person who tends to be
courteous and cheerful and gentle will continue along those lines. A coarse
braggart or a mean individual will remain the same, only with much less
inhibition. Cognitive decline mostly
lessens inhibition so that more of the underlying personality comes out. Sexual
indiscretions will be magnified early on in the disease. Insecurity and paranoia
emerges especially as regards one’s mate and accusations frequently surface,
particularly if there had been an issue from the past. Underlying depressions
and despondency will also be emphasized.
I’m not impressed that Alzheimer’s actually causes depression de novo a
lot of the time. Not always, Alzheimer patients are curiously unaware of the
loss of their own mental powers so that is more characteristic for co-workers,
family members and spouses particularly, to notice something is happening. The subject denies
the problem. This is something that clinicians have noticed in relation to
other neurological diseases and isn’t so much of a denial that something is
wrong, but not realizing that there is a problem in the first place, something
which in neurology is called anosognosia, unawareness
of one’s disease. Anosognosia occurs because of an
inability of one part of the brain where there is a problem, to communicate
with other parts that sense there is problem or at least are capable of
expressing this difficulty or may be due to a generalized impairment of
recognition of a problem. Here it may be in part due to a generalized
impairment of introspection or self-examination, a function of the frontal
lobe.
This is one distinguishing
factor of Alzheimer’s disease in fact. It’s quite common for a relatively young
person to come to a neurologist because of a problem with memory. One of the
clinical questions that always comes up is whether it’s the person themselves
who notices this memory decline, or whether there are complaints from others,
supervisors at work, friends, spouses etc.
It it’s the complainant themselves and no one else has noted the
problem, then it’s a good bet they don’t have Alzheimer’s or dementia! This young person with a memory disturbance
will, nine times out of ten either be highly perfectionistic
or have an anxiety disorder or depression. Very intelligent perfectionists may
in fact be noticing what is an inevitable but subtle age related memory
decline. Or, when someone tells them
something, they are not listening or are unable to concentrate being
pre-occupied with something else or absorbed in emotion, or, even after having
successfully registered memories are so anxious that they can’t bring memories
up, recall them, except and this is a telltale sign, later on when the pressure
is off.
The other side of the coin,
in the Alzheimer patient with less self-awareness, the anosognosia
causes more difficulties. If you don’t think there is anything wrong and others
insist that there is, maybe they are conspiring against you. Behavioral
difficulties can wear on the caretaker and cause frictions. They can be
dangerous in the sense that the person may still wish to pursue dangerous
activities such as continuing to drive or operate complex machinery. They may
insist that they can still live alone, smoke cigarettes, cook in ovens which
they leave on. These situations can be
difficult to deal with in cases where the person is insistent on having their
own autonomy and in cases where a person lives alone.
Driving is an issue in and of
itself in Alzheimer’s disease.
Generally, the Alzheimer patient should be encouraged to give up driving
sooner rather than later. You don’t want to wait until he or she gets lost or
gets into an accident due to decreased motor abilities. In one case an alert
policeman caught a patient driving confusedly the wrong direction on a 55 mph
divided highway. Fortunately no one was hurt but you don’t want to let things
get that far before you take away the keys.
Lots of clinicians have
noticed that Alzheimer patients most often have had a constricted lifestyle to
begin with. Many of them weren’t drivers in the first place. There’s the
so-called “Nun Study” which found that novitiates at a very young age who were
more unimaginative were at higher risk to develop Alzheimer disease later on.
Over the years I must say I have certainly had that impression though there are
just as many cases among geniuses with wide-ranging interests. One problem is that it’s certainly easier to
make the diagnosis of dementia in a person with limited interests and
vocabulary, what I call “cerebral reserve”, who has little redundancy in their
mental abilities and less means to hide their mental deficits.
Older folks have so much
taken away from them. I don’t see how they ever get used to it unless they also
lose (mercifully) their memory and mental faculties. Depending on their
underlying personality, taking away the car or their driver’s license can be a
big issue for a family. The doctor can help to a limited extent by standing his
or her ground. In some states the physician reports a patient to the Department
of Transportation and that is sometimes necessary. Children or other relatives
may just have to surreptitiously hide the keys or tow away the car. The same
goes for other dangers such as owning weapons or operating dangerous machinery,
using a conventional oven instead of a microwave (thank God for microwaves!),
smoking, being left alone etc.
Nowadays more adult day care
centers have been set up due to increased need and there is a variety of
nursing home units providing respite care. These units serve a definite need as
well as providing continued stimulation, something other than the omnipresent
television set, nourishing food, social interaction and easy projects and
outings to occupy the mind.
Depression occurs quite
frequently in the elderly in and out of the context of Alzheimer disease. We have some very effective drugs nowadays
with a relatively clean mode of action, not causing many adverse side effects
and with minimal drug to drug interactions. The older antidepressants drugs
like amitriptylene, nortriptylene,
imipramine are contraindicated. They are
anti-cholinergic (anti-muscarinic), sedating and will
easily affect memory and cognitive function.
SSRI’s such as Zoloft © (sertraline)
or Celexa© (citalopram)
have few interactions and work especially well. They are ordinarily pretty
neutral but may occasionally have a mild stimulating effect and increase
spontaneity.
Night-time sleeplessness can
be a terrible problem. If a confused person gets up at night there will be even
more confusion. Some persons open the door and escape the house. Rarely
patients have been known to get lost or hurt themselves. It’s very unnerving to
have grandma tooling around the house in the middle of the night or getting up
to get dressed thinking that they have to go to work or even worse, hurting
themselves in a fall or urinating on the floor. Of course, it helps to try to
keep them up and occupied during the day, to have the lights on and activity
occurring during the day in contradistinction to the night with most lights
out. The elderly person especially should be able to sleep at night with no
distractions, ought to have a regular bedtime. In other words sleep hygiene
should be enforced. Some physicians use relatively innocuous Benedryl©(diphenhydramine) for
sleep but theoretically it too is anti-cholinergic and would best be avoided.
Occasionally such newer and relatively cleanly acting hypnotics such as Ambien© (zolpidem) or Sonata© (zaliplon) (Sonata I don’t ordinarily use due to its very
short action), but I use these rarely. Desyrel© (trazodone) is also
slightly anticholinergic but it really works very
well for sleep disturbances in the elderly, is relatively mild, doesn’t affect
sleep architecture much and at proper dosage just seems to work out well in the
experience of most clinicians.
For psychosis and delirium in
and out of the hospital which Alzheimer patients are frequently heir to, some
of the older agents which used to work fairly well, haloperidol, thioridazine, Thorazine©
(chlorpromazine) are not used as much any more. The Atypical antipsychotics are currently in widespread use, not wholly
because they are new and very expensive. They do have an advantage. Risperdal© (risperidal), Clozaril© (clozapine) Zyprexa©(olanzapine), and Seroquel© (quetiapine) have been excellent. They have little if any anticholiergic effect whereas some of the older drugs
affected many different neuro-transmitters and a big
consideration is induction of Parkinsonism among anti-psychotic agents. A lot of Alzheimer patients have a movement
disorder close to Parkinson’s disease.
So-called “Diffuse Lewy Body Dementia” with
Alzheimer and Parkinson elements plus prominent visual hallucinosis
is pretty common as well so these medicines, Clozaril
© and Seroquel© especially have been a godsend. Clozaril © has been an excellent drug but the low incidence
of leukopenia dictated that biweekly blood counts be done with all
attendant paperwork. Still these new medicines are again effective and clean in
their mode of action. In a hospital
setting in the treatment of delirium we are relegated to quicker acting drugs
that can be delivered by injection such as Haloperidol or Inapsine©
(droperidol), Compazine©, Thorazine © etc. Other behavioral measures may have some
effect such as playing familiar music, having family members around and
familiar objects and repetitive relaxing activity such as massage, hair
brushing, manicure etc.
For agitation benzodiazepines
have been looked down upon for older folks but are often effective over the
short term such as Lorazepam. They can cause more confusion, no question
about that, but often work well. Buspar© (buspirone) takes a long
time to have an effect but seems to work well with patience. Various anti-convulsants
have been used extensively as well.
In summary we have advanced
in the field of treating Alzheimer’s disease. We have more effective and
cleaner acting anti-psychotic and anti-depressant drugs and the whole class of
anti-esterases provides a great advance, though
nothing close to a cure for the disease at this point.
Marginally Effective Strategies:
Home remedies, over the
counter drugs, herbs and alternative medical therapies are used extensively to
treat or prevent Alzheimer disease. Here is a mini-review of some of the more
popular approaches ranging from the least to the most promising. Extract of
Gingko biloba has become big business. Various
preparations of this very nice common garden tree are not considered drugs and
are essentially unregulated by the FDA. Consequently ingredients in each pill
or other preparation are not at all standardized and you have no idea what
kinds of impurities you are getting. One old study done on a small number of
subjects with a poor control found Gingko to be of some marginal benefit.
Otherwise evidence for effect is entirely anecdotal. Probably it can do little
harm except that it may have some anticoagulant effect and possibly interacts
with aspirin, warfarin and other anticoagulants so
that it might be marginally dangerous. I don’t recommend its use but if a
family is insistent I don’t argue either. Most families are aware of the
anticoagulant issue.
Vitamin E is an antioxidant.
Clinical benefits for a number of conditions, neurological and non-neurological
have been touted. The whole field of neuroprotection
was an exciting one in neurology perhaps ten or so years ago. So many drugs
with some anti-oxidant effect were tried for various conditions, chiefly
stroke, and not one has shown any clinical benefit. The absolute best that can
be said for vitamin E and Alzheimer’s disease is a paper by Sano et al published in the New England
Journal of Medicine in 1997 (N Engl J Med 1997; 336:1216-1222, Apr 24, 1997) showing some questionable marginal benefit but at the
relatively enormous dose of 2000 units a day. The average vitamin E pill is
200-400 units. Vitamin E has certainly a very weak effect, if any.
Alzheimer’s affects far more
women than men and occurs almost entirely after menopause. Thus there is some
suspicion that like osteoporosis, Alzheimer’s, a disease of advanced age, might
be less prevalent in women who actively preserve their youth. One way to stay
young is to continue to use female hormones which are not secreted after
menopause. The same may hold for atherosclerosis. Some retrospective studies,
chiefly the Baltimore Longitudinal Study of Aging compared women taking
hormones to those who did not and found an approximate 50% reduced incidence of
Alzheimer disease in hormone taking women. A number of studies subsequently
looked at women patients already diagnosed with dementia and failed to find an
effect of estrogens. When you do a retrospective study even with a large cohort
of persons so many things affect interpretation. The women on hormone replacement therapy are
in many ways unlike women not on it. Hormone takers may be seeing their doctors
more. They may be more health conscious, wealthier, thinner, more physically
active. The only way to study the issue is to do a large prospective study
matching treatment and control groups. Such studies are supposedly underway.
Should post-menopausal women take hormone replacement? I wouldn’t recommend it
solely to prevent Alzheimer disease at this point and certainly I don’t
recommend using estrogen after the diagnosis is made.
Non-steroidal
anti-inflammatory drugs have been talked about for a long time as possibly
preventing Alzheimer’s because, as we have seen, some of the pathology involves
inflammation. No one has proven an effect but very recently a reasonable study
was published in the New England Journal of Medicine showing as little as a 20%
incidence of Alzheimer’s among persons taking a non-steroidal agent for at
least two years. There was a time related but no absolute dose related effect.
The regular use of non-steroidals (NSAID’s) looks promising as a preventive strategy but I
would say the jury is still out. (See Breitner, JCS, and Zandi, PP NEJM
345:1567-1568 Editorial : Do Nonsteroidal Antiiflammatory Drugs Reduce the Risk of Alzheimer’s
Disease?)
Alzheimer Treatments: The Next Generation
The next generation of
Alzheimer medicines will take advantage of new understandings of the cause of
Alzheimer disease. Alzheimer’s is not a genetic disease in the sense that it
doesn’t run in families like a classic dominant or recessive trait. But there
are rare families (kindreds) in which the disease is
very common and classically inherited. These families have provided insight
into the cause of the disease. Known forms of familial
Alzheimer disease.
The first clue came from
persons with Down’s syndrome. In Down’s, which used to be called somewhat
pejoratively “Mongolism” because of some superficial facial characteristics,
there are three copies of the 21st chromosome (there should only
ever be two copies of all of our chromosomes.)
Chromosome 21 is where the gene for amyloid
precursor protein resides and hence having three copies of this chromosome
causes more amyloid precursor protein to be produced.
The treatment of many complications of Down’s patients who have relatively mild
retardation and often very positive gentle personalities has gotten better and
more are living into middle age. What has been found unfortunately, is that a
vast majority of them, perhaps virtually all, have Alzheimer disease. That was
the first hint that Alzheimer’s may in fact be caused by the accumulation of amyloid.
Recall the microscopic
changes I mentioned at the beginning of the article. Among them is the
so-called Senile plaque. This plaque is composed of a Beta-amyloid
core. The other microscopic features of the disease that is what are called neurofibrillary tangles, granulo-vacuolar
degeneration etc are not made of amyloid.
Later other genetic or
familial forms of Alzheimer disease were uncovered. We know of at least three
other genetic abnormalities which result in early onset Alzheimer disease and
these reside on chromosomes 1, 14, or 21. Chromosome 21 contains the amyloid precursor protein gene, but the others have genes
for what are known descriptively as “pre-senilins”
which only means that they code for proteins resulting fairly reliably in early
onset Alzheimer disease. The bottom line is that all of these genetic defects
cause the accumulation of beta-amyloid in the brain.
While there are other pathologic and microscopic changes in Alzheimer’s brains,
the accumulation of beta-amyloid alone seems to be a
sufficient cause, is very likely the underlying root cause, of the disease!!
This is a discovery of pivotal importance.
It means that if a method
could be found to slow or to stop the accumulation of beta-amyloid,
or to dissolve the beta-amyloid already formed then
we could prevent or retard the disease. Bear in mind that by the age of 85 depending on who is
doing the research anywhere between 1/3 to one half of all persons have
Alzheimer’s disease, that at the least, half of all nursing home residents are
there because of dementia. Alzheimer’s
even in later years, robs the next generation of contact with the wisdom and
experience of age. It abolishes the experience of age, and of course it
not-infrequently is responsible for dementia in persons as young as in their
forties and fifties.
There are a couple of heroes
in the quest for a cure for Alzheimer disease. The first is a neurologist, Dr. Stanley Prusiner winner of the Nobel Prize in Medicine in 1997.
Dr. Prusiner had spent a good deal of his academic
life studying a rare cause a rapid severe dementia, called Creutzfeldt-Jakob
disease. Creuzfeldt -Jakob
disease is caused by accumulation in the brain of Prion
Protein. This brain-destroying disease can be transmitted between mammals when this protein somehow gets into
their brains. The infection is transmitted by a protein not a virus or
bacterium and it is the cause of so-called “Mad-Cow Disease” in
A second champion is Dennis
Selkoe. He has been studying the beta-amyloid production, the enzymes involved in the
accumulation of the substance in the brain for many years. Beta-Amyloid accumulates due the action of some cell membrane
associated enzymes called Secretins. It is the Secretins
which cleave beta-amyloid from Amyloid
Precursor protein. If a short 42 amino acid strand of Amyloid
results and if it is allowed to accumulate, Alzheimer’s disease will result.
Again there is now strong experimental evidence in humans and other animals
that the accumulation of this protein, designated Aβ42 is sufficient to cause
Alzheimer disease.
The three secretins
are designated alpha (α), Beta (β), gamma(γ), the first three
letters of the Greek alphabet. These are unusual protein-cleaving enzymes
straddling through the cell membrane where amyloid
precursor protein resides. If beta secretase acts on
precursor protein first and then gamma finishes the job, the villainous
Aβ42 will form and we have the start of Alzheimer disease. If the sequence
is alpha secretase then gamma, there will not be a
problem. Therefore one reasonable strategy for preventing the disease would be
to block either the gamma or the beta secretase
enzymes. The plot thickens. It may turn out that the identity of the so-called
“pre-senilins” which mutate in genetic forms of
Alzheimer disease may really be mutant secretases.
The pre-senilins are secretases.
The senile
plaques that start as diffuse plaque that lack definite borders but later
they mature into compact plaques. The other features of the disease happen
secondarily. The plaques are formed not only from Aβ42 but are composed
debris of dead neuron extensions (neurites) and microglia, the inflammatory cells of the central nervous
system. Microscopically the neurofibrillary tangles are made of paired helical
filaments that come from broken down microtubules, the structures responsible
for moving materials around the cell. Broken down degenerated microtubles are associated with a microtubule associated
protein called tau. One test that has some utility is
measuring Tau as well as amyloid
in the spinal fluid. That gives us an indication of whether a person may have
Alzheimer disease in conjunction with Aβ42. Unfortunately levels of
patients with and without Alzheimer disease overlap quite a bit even when both
of these proteins are measured so the utility of testing spinal fluid is
limited except to help rule out other diseases like chronic meningitis and vasculitis.
Another factor that has
limited utility has made a big splash in the last few years- apolipoprotein E4. All of us have two variant genes for
this which are typed E2,E3, E4. The thinking is that apolipoproteins
that clear lipids like cholesterol. Having one of another of these genes
influences risk for accumulation of cholesterol. It also influences amyloid accumulation. It all boils down to the fact that if
you have a the E4 gene you have an increased risk of getting Alzheimer’s. E4 is
present in about two-thirds of late onset Alzheimer’s and only one-third of
controls. Having two E4 genes increases the risk of developing Alzheimer’s from
45% to 90%. So in other words the E4 gene, which we can test for, would be a
risk factor for late onset disease in much the same way that elevated
cholesterol raises the risk of heart or
vascular disease.
So given all this,
particularly that Alzheimer disease seems to be due to Aβ42 accumulation,
what would be the ultimate strategy for treatment? There are lots of
possibilities. Anything that will slow the accumulation of Amyloid,
that increases amyloid clearance will help prevent
the disease. One novel strategy that has become famous in the news is a nasally
administered amyloid vaccine. This is being studied
by Elan pharmaceuticals and involves Drs. Dennis Selkoe and Harold Weiner. The vaccine has been found
effective in an animal model of the disease, transgenic mice that were bred to
produce increased amyloid and showed a 50% reduction
in senile plaque formation and improvement on tests. It is now in clinical trials in humans and
does look very promising.
Otherwise it is possible to affect the secretases. Amgen is testing a beta-secretase inhibitor and Bristol-Meyers Squibb has a gamma secretase blocker in testing. Beta-Amyloid is also seen as a metalloprotein