13 Nov 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 231 (p-tau231) in the cerebrospinal fluid of patients. Harald Hampel of Ludwig-Maximilian University in Munich, Germany, presented data on two multicenter 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 added.

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

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Papers

1. Klunk WE, Bacskai BJ, Mathis CA, Kajdasz ST, McLellan ME, Frosch MP, Debnath ML, Holt DP, Wang Y, Hyman BT. Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J Neuropathol Exp Neurol. 2002 Sep;61(9):797-805. PubMed.