13 November 2001. One of the most coveted achievements AD researchers are
striving for these days is to develop a biomarker that could, simply and
inexpensively, detect if a person has early Alzheimer's disease. Such a test
would firm up a currently subjective diagnosis and make it possible to
assess the efficacy of experimental therapies and track disease progression.
Tau in Cerebrospinal Fluid
One such approach involves measuring levels of tau phosphorylated at the
amino acid site threonine 32 (p-tau231) in the cerebrospinal fluid of
patients. Harald Hampel of Ludwig-Maximilian University in Munich, Germany,
presented data on two multi-center trials evaluating this method. One study
looked at its ability to distinguish Alzheimer's from other types of
dementia, including frontotemporal dementia, Lewy-body dementia, and
vascular dementia, in 192 people. Hampel et al. report that measuring this
phosphorylated version of tau, which is linked to early AD pathology,
increased the number of correctly allocated cases from 66 percent to 90
percent as compared to total tau. Testing 17 AD patients annually for up to
six years suggested that P-tau231evels decrease over time, probably
reflecting the massive loss of neurons in progressing AD.
The second trial asked how well this method could predict future decline in
people with the earliest signs of cognitive damage. This study enrolled 319
people who were either healthy, had mild cognitive impairment, or AD, then
measured their p-tau231 at baseline and followed those with MCI for three
years. Hampel et al. report that high baseline levels of p-tau231, but not
of total tau, predicted future cognitive decline, as did ApoE4 status.
Peter Davies at Albert Einstein College of Medicine in New York, who
provided an antibody used in the method, believes this approach may be
useful in early diagnosis, especially since the range of p-tau231 levels
across people with early AD does not overlap significantly with the range
seen in controls. (This problem besets other approaches, for example
measuring CSF Aβ42 levels.) It won't be suitable for screening
populations of people, however, because it requires a spinal tap. The test
is commercially developed, and results come back within a few days, Davies
Not Just Science Fiction: Look at the Living Brain and See the Plaques
Wouldn't it be nice if a person noticing the first worrisome signs of
cognitive decline could simply have a laser beam shone right through his/her
skull to see if there is amyloid? While this is clearly not around the
corner, Brian Bacskai gave a talk this morning in which he described a way
of doing it in mice.
Working with Brad Hyman at Massachusetts General Hospital in Boston and
others, Bacskai injected the lipophilic small molecule methoxy-XO4
(originally developed by coauthor Bill Klunk at the University of
Pittsburgh), into the veins of transgenic PS1/APP mice expressing plaques in
their brains. Bacskai used multiphoton microscopy, which can image, at
subcellular resolution, the top cortical layers of living mice through a
hole in their skull. He saw that methoxy-XO4, which is fluorescent, had made
its way to the brain and was labeling plaques within the hour of injection.
When imaging the day after injection, the procedure routinely yielded
high-contrast images of plaques and cerebrovascular amyloid, the scientists
report. When applied to post-mortem sections of AD brain, the compound
labels plaques and tangles with high sensitivity. An earlier candidate,
congo red, has not proven to work.
One way to develop this compound into a biomarker would be to radiolabel it
with technetium for use in PET scanning. However, even the development of a
multiphoton microscope that can image the human brain through the intact
skull is becoming technically conceivable, said an optimistic Hyman.-Gabrielle Strobel.
Reference:Blennow K, Vanmechelen E, Hampel H. CSF total tau, Ab42 and phosphorylated tau protein as biomarkers for Alzheimer's disease. Mol Neurobiol 2001 Aug-Dec;24(1-3):87-97. Abstract
Hyman BT et al. Imaging Ab plaques in living transgenic mice with multiphoton microscopy using the peripherally administered congo red analog, methoxy-XO4. J Neuropathol Exp Neurol. 2002 Sep;61(9):797-805. Abstract