Molecular probe identifies patients at risk of Alzheimer's

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Protein plaques and tangles tracked in live brains for first time

A new molecule could provide an early warning system for Alzheimer’s disease, US researchers hope.

Two proteins, β-amyloid and tau, are thought to play a key role in the development of Alzheimer’s disease (AD). During the course of the disease abnormally-folded deposits of these proteins form ’plaques’ and ’tangles’ in the brain. The new compound, developed at University of California Los Angeles (UCLA), known as FDDNP, has for the first time allowed detection of both these deposits in the brains of live patients who might be years from developing the disease.

FDDNP contains the radioactive element ¹⁸F, which emits positrons, or gamma radiation. It is adept at crossing the blood-brain barrier, and seeks out and binds to the problematic proteins. Areas where the molecule has accumulated can be imaged by detecting its radiation signal with positron emission tomography (PET).

The UCLA study, led by Gary Small of the Semel Institute for Neuroscience and Human Behavior followed 83 patients over two years who were suffering from mild cognitive impairment (MCI), a condition that often develops into AD. Following injection, PET detected FDDNP in parts of some MCI patients’ brains suggesting plaques and tangles had already formed. Follow-up scans on the same patients who had gone on to develop AD revealed the PET signal was stronger in the same areas. Crucially, autopsy of one of the subject’s brains confirmed that the areas showing a high PET signal contained the deadly deposits. ’This is the first time this pattern of plaque and tangle accumulation has been tracked in living humans over time,’ said Small.

Creating organic compounds with radioactive atoms attached produces some interesting challenges for UCLA’s Jorge Barrio. His group developed the FDDNP synthesis and was among those that pioneered the use of positron emission in biomedicine. ¹⁸F is produced at UCLA’s cyclotron. It has a half-life of about two hours, so attaching it to a molecule has to be done at the last possible moment before the compound is rushed to the patient. ’When you have a patient waiting, having the chemistry going is like starting the car in the morning - it has to go!’ said Barrio. So speed, safety, and reliability are all vital. His group has developed an automated synthesis of FDDNP that Barrio said is ’idiot-proof’. The remote-controlled system limits technicians’ exposure to radiation and produces chemically and radiochemically pure FDDNP in a sterile solution that is safe for injection into a patient.

Small’s team found that their new system could differentiate between MCI, AD and normal ageing more accurately than other diagnostic methods currently used by clinicians. It was more reliable than magnetic resonance imaging (MRI) and another PET marker known as FDG which is used to identify areas of abnormal glucose metabolism in the brain. Large clinical trials will begin shortly, which Small hopes will confirm his technique’s reliability and maybe shed more light on the link between MCI and Alzheimer’s.

Small told Chemistry World he believed the technique ’may allow us to identify potential candidates for treatment before serious brain damage occurs’ as well as helping to test new treatments. Drugs are being developed to combat the formation of these brain deposits. If they become widely available, Small hopes his early-stage ’brain check’ will become as common as a cholesterol test is today.

Clive Ballard, director of research at the Alzheimer’s Society, UK, said the study was exciting. ’The ability to diagnose at the earliest possible stage is of huge importance,’ he said. ’We look forward to further developments in this area of research.’

Tom Westgate