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Alzheimer's, Dementia & Mental Health
Alzheimer’s Disease May Be Identified by Protein
‘Fingerprint’ in Spinal Fluid
Test for spotting early Alzheimer’s disease could
be in the not-too-distant future
December 12, 2006 – The battle against Alzheimer’s
disease, the mind-clogging ailment most feared by senior citizens – has
often focused on finding a means of early detection, when there seems to
be more of an opportunity for treatment. Scientists have now identified
a panel of 23 protein biomarkers in cerebrospinal fluid that acts as a
neurochemical “fingerprint,” which doctors may be able to use someday to
identify patients living with Alzheimer’s disease.
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Alzheimer's, Dementia & Mental Health |
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Today, physicians must rely on their clinical
judgment to decide whether a particular patient has Alzheimer’s rather
than some other form of dementia. In many cases, the diagnosis remains
uncertain until brain tissue is examined at autopsy.
The research by scientists collaborating at Cornell
University in Ithaca and Weill Cornell Medical College in New York City
will be published in the December online-edition of the journal Annals
of Neurology.
“Our study is the first to use sophisticated
proteomic methods to hone in on a group of cerebrospinal fluid
biomarkers that are specific to autopsy-proven Alzheimer’s disease.
Those postmortem tests confirmed that the panel is over 90 percent
sensitive in identifying people with Alzheimer’s disease,” says Kelvin
Lee, the Samuel C. and Nancy M. Fleming Professor of Molecular and Cell
Biology and associate professor of chemical and biomolecular engineering
at Cornell.
Researchers at a variety of centers have long
sought biomarkers in blood or cerebrospinal fluid that identify the
presence of Alzheimer’s pathology and distinguish it from other
conditions that cause dementia.
“Some of these studies have met with limited
success, but most have correlated their findings with patient’s clinical
symptoms rather than working with the gold-standard of autopsy-proven
Alzheimer’s,” notes Norman Relkin, M.D., associate professor of clinical
neurology and neuroscience at Weill Cornell and director of the Memory
Disorders Program at NewYork-Presbyterian Hospital/Weill Cornell Medical
Center.
Erin Finehout, Ph.D., the lead author on the
research who had been a doctoral student in Lee’s laboratory, said this
has great potential to impact human health.
“Typically, Alzheimer’s disease is not diagnosed
until the disease has already caused some amount of dementia,” she said.
“Having a chemical test available may allow patients to be diagnosed
earlier in the course of the disease.”
The Cornell study combined cutting edge
“proteomics” technology, detailed image analysis, and complex
computational and statistical analyses to simultaneously compare 2,000
cerebrospinal fluid proteins from 34 patients with autopsy-proven
Alzheimer’s disease to those of 34 age-matched controls without the
disease.
“Just as the human genome reflects the array of
genes a person possesses, the ‘proteome’ is the vast collection of
proteins expressed by those genes,” said Lee. “Essentially we used
high-tech methods to contrast the proteomes of Alzheimer’s patients
against those of a control cohort that included people with other forms
of dementia as well as healthy individuals, looking for key differences
between the two groups.”
This effort yielded intriguing results: 23 proteins
that individually might not point to Alzheimer’s but together formed an
identifying pattern or “fingerprint” specific to the illness.
“Although it need not have turned out that way,
several of the 23 markers that emerged from this analysis proved to be
proteins with known links to the pathological mechanisms of Alzheimer’s
disease,” said Relkin.
For example, some of the biomarkers are associated
with proteins that clog the brains of Alzheimer’s patients. Others
molecules were linked to inflammation, also a part of Alzheimer’s brain
pathology. Still other proteins in the panel were linked to synaptic
dysfunction – the breakdown of communication between brain cells that
occurs as Alzheimer’s disease progresses.
“A subsequent validation group of 10 patients with
suspected Alzheimer’s and 18 healthy and demented control subjects
turned up similar results,” said Relkin. “Based on their clinical
symptoms, we found the new screen to have 93 percent sensitivity to
probable cases of Alzheimer’s and a 90 percent accuracy in avoiding
false diagnoses.”
Despite their excitement over the new findings, the
researchers stress that the results still need to be replicated in much
larger populations.
“There’s a federally funded, multicenter trial
going on right now that involves many more patients, in which many
enrollees will undergo spinal taps and brain imaging,” Relkin said. “We
hope to link into that effort to expand on these findings.”
The dream of a highly accurate Alzheimer’s disease
test that patients and doctors could use to diagnose illness and guide
treatment is the ultimate goal. But the finding has important
implications for current Alzheimer’s research, as well.
“You might have a promising treatment for the
disease, but how can you know for sure that it’s impacting on the
underlying pathology, rather than just easing outward symptoms as most
of the drugs that we have now do?” Relkin said. “We are hopeful that by
monitoring changes in these cerebrospinal biomarkers, we can actually
track the effectiveness – or lack thereof – of experimental drugs.”
He continued: “In fact, we are now using this panel
to study the effects of a promising new experimental treatment for
Alzheimer’s called IVIg (intravenous immunoglobulin). “Data gleaned from
the use of this 23-protein screen suggests that IVIg may be having a
positive impact on underlying disease processes.”
And while a standard test for spotting early
Alzheimer’s disease is not in doctors’ offices today, it could be in the
not-too-distant future.
“These findings speak to the practicality of using
biological markers for discerning whether symptoms are reflective of
Alzheimer’s, another dementia or normal aging,” Relkin said. “And in
this study, we’re offering a much more sophisticated and
better-validated approach than has ever been presented before.”
The other researchers include: Zsofia Franck and
Leila Choe of the School of Chemical and Biomolecular Engineering at
Cornell.
This work was funded by the Michael J. Fox
Foundation; the O’Neill Foundation; the New York State Office of
Science, Technology and Academic Research; Cornell University; and the
U.S. National Institutes of Health.
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(866-697-6397).
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