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THIS STORY HAS BEEN FORMATTED FOR EASY PRINTING
Inside the damaged brain New dynamic imaging techniques provide a deeper look at Alzheimer's and schizophrenia By Robert Adler, Globe Correspondent, 5/6/2003 Paul Thompson, the UCLA neuroscientist whose team created these
first-ever sequences of a disease engulfing the living human brain, sees
them as a significant step toward earlier diagnosis, more effective
treatment, and -- eventually -- prevention or cure of brain-destroying
diseases.
Sid Gilman, director of the Michigan Alzheimer's Disease Research
Center, concurred. ''The images are pretty dramatic,'' he said, ''and what
they show is very important.'' With 10 million Alzheimer's cases expected
in the United States by 2025, progress is vital.
Thompson, a 31-year-old British emigrant, is unabashedly excited about
his team's accomplishments: ''The tools from our group are opening really
new windows on what's happening inside the brain.'' They give researchers
a powerful way to test new medications and lets doctors diagnose
Alzheimer's and other dementias earlier and more accurately. That should
give more patients an early start on medications that can at least slow
the ravages of these diseases.
Like faces, no two brains are alike. As a result, it's extremely
difficult to compare diseased and healthy brains or track changes over
time. That's the problem Thompson and his team solved. By morphing
ordinary MRI scans onto a standardized brain, they can pool scans from
multiple patients without blurring the picture. They can then sequence
those standardized images into revealing movies. And, crucially, they can
quantify changes with great precision. ''We can code normal human
variation,'' he said, ''and still be exquisitely sensitive to abnormal
changes.''
As a result, Thompson's group has been able to study diseases such as
Alzheimer's and schizophrenia as never before. ''With this kind of
imaging, you can see a lava flow of destruction as more and more brain
tissue is engulfed,'' Thompson said. ''You can see exactly which areas are
losing tissue, when, and how fast.''
Thompson first applied these new tools to schizophrenia, a
life-changing illness that strikes about one young person in a hundred
worldwide. Researchers continue to debate schizophrenia's causes. It can
devastate thinking, feeling and behavior without causing obvious brain
damage. Some imaging studies showed thinning of the cortex, the brain's
outer layer. Others saw a shrunken hippocampus -- a nubbin of tissue deep
within the brain that is vital for storing memories. Until recently, these
findings created more controversy than clarity.
In 2001, Thompson's group produced the first time-lapse images
revealing a wave of tissue loss rolling across the brains of schizophrenic
children. They utilized high-resolution MRIs of more than 1,000 children
scanned every two years since 1992 by Judith Rapoport and colleagues at
the National Institute of Mental Health. Thompson's group detected the
first flicker of the disease in a small part of the parietal cortex, above
and behind the ears.
Over five years, Thompson saw a ''pervasive, unrelenting wave of tissue
loss that swept forward like a forest fire,'' eventually engulfing the
sides and front of the brain. By 18, the teenagers had lost 25 percent of
their gray matter in certain brain areas.
''Seeing that wave of tissue loss in schizophrenia was a huge
surprise,'' Thompson said. The pattern matched the drumbeat of
schizophrenia's active and passive symptoms -- hallucinations, delusions
and bizarre thinking followed by flattened emotions, depression and
withdrawal.
The images are disturbing but valuable. They've pushed Thompson toward
the theory that schizophrenia is a disrupted version of normal brain
development.
Teenagers' brains normally undergo extensive ''pruning'' in which 1
percent of the gray matter disappears every year, more in some areas.
Because schizophrenia typically strikes during this process, Thompson sees
it as ''an exaggeration or derailment'' of normal pruning -- like a
gardener gone wild.
His finding that schizophrenia takes up to seven years to engulf the
brain highlights the need for early diagnosis and treatment. It also makes
finding drugs that may salvage young people's brains even more vital.
''There is a window of opportunity to step in and oppose the disease,'' he
said.
Unlike schizophrenia, Alzheimer's usually strikes the elderly and often
leads to death. Since pathologists have autopsied the brains of thousands
of Alzheimer's patients, Thompson knew what his movies ought to reveal. As
reported in the Journal of Neuroscience earlier this year, the tissue
losses he found in living patients tracked the autopsy studies almost
perfectly. The new images also made sense of the dreaded progression of
Alzheimer's symptoms. Early memory and emotional problems matched damage
deep within the brain. Erosion of higher mental functions mirrored a wave
of damage that swept across the parietal and temporal lobes on both sides
of the brain, inundating the language-processing left hemisphere first. By
the time the disease engulfed patients' frontal lobes, their personalities
and lives were shattered.
Thompson thinks the findings offer a clue to what causes Alzheimer's.
The wave of gray-matter loss he saw matches the spread of beta-amyloid
plaques through the brain, supporting the theory that the build-up of that
abnormal protein is a key to the disease. That makes treatments that
target amyloid, including a controversial vaccine, look more promising.
Although the new imaging technology is powerful, sophisticated and
dramatic, it's just one step toward the prevention or cure of Alzheimer's,
schizophrenia, and other brain-killing diseases. The work's first
application may be in the early detection of these diseases, allowing more
people to benefit from medications that slow the progress of schizophrenia
and Alzheimer's. The new scans also will help researchers evaluate current
and future drugs. Precision measurements of gray matter saved or lost
gives drug researchers a clearer target to aim for.
Dynamic brain imaging should also speed up the search for genes that
predispose people to specific brain diseases. We know they're there.
Siblings and children of schizophrenics have one chance in 10 of
developing the disease -- 10 times the average risk. A half-dozen genes
already have been linked to Alzheimer's, with more to come. It is much
easier to match suspect genes to specific patterns of tissue loss than to
shifting, hard-to-measure symptoms.
Adam Boxer, a neurologist at the Memory and Aging Center of the
University of California at San Francisco, ''I'm very excited by this
technique,'' Boxer said. ''We know a lot about the molecular biology of
Alzheimer's, but we don't understand on a millimeter-by-millimeter scale
how it affects the living human brain.'' Thompson's revealing movies and
the methodology behind them bring us closer to that goal.
Thompson's movies can be viewed at
www.loni.ucla.edu/thompson/AD--4D/dynamic.html, and
www.loni.ucla.edu/thompson/MOVIES/SZ/sz.html.
This story ran on page B11 of the Boston Globe on
5/6/2003. |