Photo by Mark Hooper
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Inside Jim’s Brain
By Jim Thornton, September & October 2005
How scientists are untangling the mysteries of Alzheimer’s
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Read All Articles in This Special Report
What It Feels Like: A Personal Account of Living With Alzheimer's
He's Still in There: A Daughter's Perspective
Stay Sharp Longer: Nine Simple Things You Can Do
Finding Help: New Choices for People With Early-Stage Alzheimer's
Great Pretenders: Common Ailments and Drugs Known to Monkey With Memory
Web Exclusive: Feed Your Head With Healthy Brain Foods
Back to the first article in this Special Report: You’re Wiser Now
In the middle of a six-hour car trip to the National Institute of Mental
Health (NIMH) in Bethesda, Maryland—where I will volunteer for a study on
Alzheimer's disease—I pull over to buy gas. My nerves are already
rioting. Over the next few days, I'll be subjected to cognitive tests,
functional assessments, physical exams, genetic analysis, an MRI, and a spinal
tap. Maybe it's panic over this daunting inquisition of body and
mind—not to mention the dire news it might reveal about my
future—that causes the mental lapse: when I reach down to unlatch the gas
tank, I can't find the latch. I've owned this car for a decade,
I've pumped gas thousands of times, and now I'm unable to execute a
maneuver that should be rote. It takes five frantic minutes before the
latch's location finally burbles up through my synaptic fog.
The brain freeze is alarming coming so soon before the National Institutes
of Health's (NIH) mental boot camp. The family study in Bethesda is one of
many scientific investigations worldwide shedding new light on Alzheimer's.
Trey Sunderland, M.D., chief of NIMH's geriatric psychiatry branch, first
launched this study in 1995. Its official name is the BIOCARD study, an acronym
for "Biomarkers for Older Controls at Risk for Dementia." NIMH
researchers will follow the same volunteers year in and year out until we die.
The goal is to witness AD in transition, discover its early predictors, and
find new ways to delay the brain's deterioration.
When I first asked about volunteering, Sunderland told me that 3 to 4
million Americans currently suffer from AD. "If nothing else happens to
slow the rate of new cases," he added, "our country could have
between 12 and 16 million people with AD in the next 30 years. Such a huge
increase would overwhelm the medical and nursing home systems and financially
overwhelm many families."
In hopes of doing our part to help forestall this demographic train wreck,
250 of us make yearly treks to Maryland for three days of tests. The group is
divided into three subgroups: those already suffering from dementia symptoms;
those without symptoms or a family history of the disease; and those, like me,
whose parents or siblings have been diagnosed with probable AD.
As a member of this last group, I have a fourfold-increased risk of
developing AD. My father, a Yale-educated engineer and one of the smartest
people I've ever known, once suffered minor memory glitches like the one I
just had at the gas station. By his late 70s, such glitches had become more
rule than exception. His memory continued to decline until he needed constant
care, an ignominy that he largely bore with grace and good humor until he died
at age 81.
During the long drive across Pennsylvania into Maryland, I find myself
praying that the upcoming battery of tests will find me still normal. It's
not an easy hope to hold on to. When I reach the motel lobby, a clerk hands me
a parking pass and tells me to hang it on my rearview mirror. I head back to
the car to do so. Somewhere during the 25-foot journey, I lose the pass. After
a 10-minute search, I ask for a replacement.
The next morning, the hotel shuttle circumnavigates the NIH campus,
eventually spilling me out at the doorstep of the clinical center. It takes 10
minutes of meandering through this multilevel maze to find the designated unit,
and I wonder if my cognitive testing has already begun. Surely a guy with
normal hippocampal volume—which Alzheimer's gnaws away—could
have made this journey in eight minutes or less.
I try to remain optimistic. Researchers at the NIH and around the world have
made remarkable strides toward understanding the disease first described by
German psychiatrist Alois Alzheimer in 1906. As Alzheimer discovered, patients
with AD have two types of brain abnormalities. The first is a plaque made up of
beta amyloid, a gummy protein that accumulates outside of nerve cells. When the
immune system steps in to clean up the mess, the brain becomes inflamed. As the
battle rages, dead and dying parts of once healthy brain cells, along with
other debris washed in by the bloodstream, cluster together into denser
plaques. Over time, the brain becomes riddled with these plaques.
The second type of brain dirt comes in the form of molecular tangles, which
occur inside brain cells themselves. Normally, a protein called tau acts like a
miniature I-beam to stabilize the internal structure of these cells. Just as an
I-beam can sometimes rust, twist, and collapse, so too can tau deteriorate.
When this happens, the once straight molecules become kinky and collect
together in thick, ropy structures known as neurofibrillary tangles.
"These tangles just choke the cells to death," explains Steve
DeKosky, M.D., director of the Alzheimer Disease Research Center at the
University of Pittsburgh.
There are other, rarer forms of dementia whose victims suffer only plaques,
only tangles, or even completely different species of molecular brain dirt. But
to have AD, you need, by definition, to have both plaques and tangles in your
brain.
And herein lies a huge problem for doctors and researchers alike: how can
you know for certain if a patient's brain is filled with crud? Plaques and
tangles don't show up on x-rays or other noninvasive scans, so for now
there are only two sure-fire ways to detect their presence: autopsy the brain
after a patient has died or do a kind of core-drilling surgery while the
patient is alive. For obvious reasons, the latter is rarely an option.
That's why scientists have long sought one of the Holy Grails of AD
research: a way to diagnose the disease without having to directly sample brain
tissue. Seeking to uncover such a marker, as I am soon to discover, the BIOCARD
study casts an unusually large and fine-meshed net.
I'm greeted by nurse practitioner Irene Dustin and Joyce Deleeuw, R.N.,
two of the many NIH staffers who will serve as my handlers over the next couple
days. Dustin takes my personal and family history—the full catastrophe,
as Zorba the Greek once put it. We then proceed to the Mini-Mental State Exam,
a deceptively simple test invented in 1975 by Johns Hopkins psychiatrist
Marshal Folstein. The Folstein, as it's also called, is possibly the single
most-used cognitive assessment in human history. Despite its
simplicity—the questions take only 5 to 10 minutes—the Mini-Mental
provides an excellent quick-take picture of brain health.
Dustin asks me the date, then the state and county we're in. I manage to
repeat the words "horse, purple, honesty," count backward from 100 by
7s, point to a pencil and a wristwatch, and answer other interrogatories. Just
when it seems I'm home free, Dustin asks me to repeat the three words she
told me earlier on. It takes a few panicky seconds to remember them, but
finally the image of an honest purple horse surfaces to consciousness, and I
get this one right too.
Twenty minutes later, I find myself in the testing chamber of occupational
therapist Frances Oakley. "My job," Oakley explains, "is to look
at the activities of daily living, or ADL—the things we all do day in and
day out." Oakley hands out a questionnaire on bathing, dressing,
toileting, walking, eating, sleeping, grooming, home care, money management,
and so forth. Though I suffer no impairment in any of these areas, I realize
the number of skills a human needs to master is daunting.
Oakley next guides me to the "hands-on" portion of her lab, which
is a perfect replica of a suburban kitchen. The goal here is to do something
useful while Oakley monitors my performance. "We have 80 different
possibilities," she says. After surveying the list, I pick one close to my
heart: cooking breakfast.
During the last year of my father's life, I made him breakfast every
morning: eggs sunny-side up, two pieces of toast, a glass of orange juice, and
coffee. As I settle into the familiar routine, Oakley takes detailed notes.
She's looking at 16 separate motor skills. For example, can I reach for a
cup without difficulty? Do I have the dexterity to grip the spatula? Oakley is
also analyzing my performance of 20 different "process" skills. Am I
cooking eggs, not pancakes? Am I following a logical sequence?
When I finish, Oakley says she hasn't seen any obvious impairments. So
far, so good. The tests have not completely ruled out the presence of gunk in
my noggin. But if plaques and tangles are silently accumulating, at least they
don't seem bad enough yet to impair my functioning in obvious ways.
Researchers are feverishly working on treatments to halt AD well before a
patient loses the ability to cook eggs. A therapeutic vaccine targeting beta
amyloid worked well in mice, but a trial in humans was stopped in early 2002
after 18 of 300 participants developed brain inflammation. That vaccine has
been abandoned, but the strategy of harnessing the patient's own immune
system is still being pursued. Rather than use a vaccine to spur the immune
system to create antibodies, two pharmaceutical companies, Elan and Wyeth, are
funding studies in which antibodies are directly infused into Alzheimer's
patients.
Other researchers suspect patients with AD may suffer a defect in a specific
type of immune cell that, when working correctly, gobbles up excess beta
amyloid. In a study published last June, researchers at the University of
California, Los Angeles, showed that these housecleaning immune cells, known as
macrophages, work fine in normal people but not in AD patients. Their research,
though still preliminary, holds hope for new ways to attack the disease.
On the genetic front, at least three mutations have been discovered that
doom their owners to early-onset Alzheimer's. This rare form of the disease
can strike people at age 40 or even younger. Researchers have also made strides
in identifying genetic risk factors for late-onset AD, which develops after age
65. One gene known as APOE comes in three different forms. Everyone has this
gene, but, depending on the forms you inherit, your susceptibility to
late-onset AD either increases or decreases. How APOE works to increase or
decrease vulnerability represents another hotbed of promising research.
Scientists had high hopes that two classes of drugs commonly used for other
conditions—anti-inflammatories and cholesterol-lowering statin
drugs—might significantly delay AD symptoms or even prevent some cases
from ever developing. Unfortunately, no such benefit has yet been proven for
anti-inflammatory drugs. But some studies of statin drugs have found that they
do protect against dementia. (Other studies found no such link.) Researchers
theorize that these drugs may reduce beta amyloid levels in the brain and
increase blood flow.
For patients already diagnosed with AD, the FDA has approved two different
classes of drugs. The first class includes Aricept, Exelon, Reminyl, and
Cognex, which all work by delaying the breakdown of a brain chemical called
acetylcholine. Acetylcholine helps nerve cells to communicate, and it plummets
in AD patients. The second class, approved in October 2003, is being marketed
under the name Namenda. This drug works by decreasing glutamate, yet another
brain chemical that appears to overly excite nerve cells and, in the long term,
kill them.
Though neither of these classes of medicines falls into the "miracle
drug" category, they do slow the progress of AD symptoms somewhat. And
such drugs represent just the iceberg's tip of things to come. One example
is an experimental drug called Alzhemed, which blocks the accumulation of beta
amyloid. Preliminary results have shown that it can stabilize or improve
cognitive function in AD patients. As researchers continue to unravel the
complexities of plaques and tangles, reason for hope will surely grow.
A technician is siphoning blood from my arm. Besides scrutinizing it for the
usual—abnormal cholesterol, sugar levels, electrolytes—the
researchers will also examine my DNA, including my APOE genes. APOE is by no
means a foolproof predictor of Alzheimer's. People blessed with the
"good" kind sometimes develop AD; those with the "bad" kind
sometimes avoid it. To keep from raising false hope or causing anxiety, the
researchers will not divulge my APOE status—which is A-okay by me.
I spend the rest of the afternoon undergoing cognitive tests delivered by a
shifting array of neuropsychologists. I memorize lists of words, try to discern
if rotated patterns on a computer screen are the same, list all the items I can
think of in a grocery store. By the time dinner rolls around, my brain feels
like a bruised fruit.
As Sunderland later explains, this exhaustion is no accident. "We need
to stress you with testing to see the limits of your memory," he says.
"That way, when we follow you over time, we can see even slight
deflections from the very high level of memory most of our subjects come into
the study with."
By 9 p.m., despite my weariness and a lingering headache, I'm undergoing
an MRI. Mercifully, the technician gives me earplugs. The MRI blasts a series
of bangs, chimes, and clicks, like a hideous rock concert performed by apes. I
am motionless as a corpse; the last thing I want to do is mess up and have to
go through this again.
Painless scans such as this may one day predict dementia. Last summer,
scientists at New York University reported that positron emission tomography,
or PET, scans showed reduced activity in the brain's hippocampal area many
years before patients developed symptoms of Alzheimer's disease.
At the end of my MRI, the tech displays an image of my brain on his
computer. My brain looks much smaller and less wrinkled with cerebral
convolutions than I'd hoped: no challenge to Einstein here. With this
somewhat disappointing image of my mind in mind, I return to my room in the
clinical center, take some ibuprofen, and lay my aching head down for the
night.
Deleeuw wakes me at 7 a.m. to prepare me for a spinal tap, which proves a
breeze. It takes about half an hour to remove 20 cubic centimeters of fluid,
which looks like water. As clear as the samples appear, they contain a
treasure-trove of sugar, proteins, and neurotransmitters that the researchers
will scrutinize for potential AD markers. BIOCARD researchers are particularly
interested in two specific compounds floating about in this broth, which bathes
both the spinal cord and the brain. You guessed it: beta amyloid and tau, the
building blocks of brain dirt.
Preliminary data now indicate that low levels of beta amyloid and high
levels of tau protein in the spinal fluid may be associated with increased risk
of developing AD. As is the case with other potential—though not
certain—risk factors such as APOE type, my results here won't be
divulged to me. Some of the fluid sample will be frozen for future
analysis—that is, when and if new markers are discovered that might play
a role in AD risk.
After the spinal tap, it's back to high-order cognitive testing. At some
point, I notice the first stirrings of a slight headache. By 4 p.m. I can no
longer ignore a slowly intensifying migraine. While in the midst of a
computerized test administered by a graduate student from nearby Catholic
University, I finally give up.
"I'm sorry," I say, "my head hurts so much, I gotta lie
down."
Back in my room, Ted Huey, M.D., a clinical fellow at NIH, questions me
about my symptoms. He's concerned that the pain might be associated with
the morning's spinal tap, but concludes I'm probably suffering a
tension headache. By the next morning, his diagnosis seems correct: I awaken
feeling fine again.
On this, the third and final day of testing, my only remaining contributions
to science are two additional blood draws. Afterward, Sunderland shares the
various remaining results that can be divulged. At one point, he even uses the
phrase "completely normal" to describe me, which is something of a
first.
Back at the hotel that afternoon, I manage to find my car without a problem.
But over the next few days, the headaches continue. A concerned Huey calls
regularly to check in and offer advice. His new diagnosis: the spinal tap,
along with stress and dietary changes, has triggered a recurring
migraine/tension headache. He suggests I try alternating doses of ibuprofen and
Tylenol. It works: five days later, I'm pain-free.
Thanks to that five-day headache, I had pretty much decided never to return
to Bethesda. But as the months have passed, I've reconsidered. My dad bore
the considerable burdens of his final years without complaint. Surely I can
continue to participate in a study that offers so much promise to so many
people. So when a year rolls around, I'll go back to
Bethesda—provided, that is, I can still find the gas tank.
Jim Thornton, who lives near Pittsburgh, Pennsylvania, writes regularly
about medical topics for Men's Health and Field &
Stream.
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