For the first time, researchers have succeeded in passing an antibody through the blood-brain barrier to act as a tracer for PET imaging of the brain. This resulted in more precise information being obtained than with regular radioactive tracers. The study provides hope for more effective diagnosis of early onset Alzheimer’s disease and improvements in monitoring the effects of medication.
In the new study, published in Nature Communications today, Uppsala researchers demonstrates that an antibody gives more exact information than regular radioactive tracers used in PET brain scans.
“The major advantage of monoclonal antibodies compared to regular small molecule PET tracers is their very high specificity. Our antibody binds soluble forms of amyloid beta, so-called protofibrils, which are probably the toxic form of amyloid and which cause the symptoms,” says Lars Lannfelt, professor of Geriatrics at Uppsala University and a chief consultant at Uppsala University Hospital.
Positron emission tomography (PET) as a method for diagnosing Alzheimer’s disease has made rapid progress in recent years. The person being examined is administered with a radioactive tracer, most often via a blood vessel. Using the PET scanner, it is possible to see how the tracer is taken up by and distributed within cells or organs.
The new PET method has been developed by researchers working at the PET Centre at Uppsala University and Uppsala University Hospital. This is the first time that a monoclonal antibody has been used for PET imaging of molecules in the brain. Such antibodies are sometimes used as tracers, but usually in order to diagnose cancerous tumours in the body. In the brain, however, the uptake of antibodies is limited by the blood-brain barrier. In order to get through this, researchers have developed a fusion protein which increases the passage by a factor of about 15. Like a Trojan horse, an antibody is administered to the brain via another antibody which deceives a receptor on the vessel wall. The study has been carried out using live transgenic Alzheimer mice.
“Compared to traditional tracers which give more statistical/unchanging signals as the disease progresses, with our method you can monitor its progression. This is a great advantage since the symptoms of Alzheimer’s disease often appear gradually over a period of 10-20 years. The method much increases our ability to see the progress of the disease and to assess the effects of medication,” says Associate Professor Stina Syvänen.
The researchers are currently working on a similar PET method for Parkinson’s disease. In the future, it is expected that it will be possible to examine other brain conditions using these techniques, for example, depression and bipolar disorder.
About this Alzheimer’s disease research
Several new pharmaceuticals for treating Alzheimer’s disease are undergoing clinical phase II and III testing. Their development is made more difficult as there are no methods for measuring their effects on patients at molecular level.
A new monoclonal antibody, BAN2401, developed in Uppsala, is currently being tested in a major international study involving approx.. 800 patients in Europe, Canada, Japan and the USA. In Sweden, three University Hospitals are involved. Uppsala, Sahlgrenska (Göteborg) and Skåne (Malmö/Lund).
Almost 100 000 people in Sweden have Alzheimer’s, the most common dementia disorder. Of the over 65s, almost five percent have the disease, of the over 80s around every fifth person.
Normal early symptoms are memory loss, for example, difficulty finding well-known places. In the later stages, language ability deteriorates; motor skills are affected; difficulties arise in recognising people and understanding things. In the end, the sufferer becomes bedridden.
Source: Lars Lannfelt – Uppsala University Image Source: The image is in the public domain. Original Research: Full open access research for “Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease” by Dag Sehlin, Xiaotian T. Fang, Linda Cato, Gunnar Antoni, Lars Lannfelt and Stina Syvänen in Nature Communications. Published online February 19 2016 doi:10.1038/ncomms10759
Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease
Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood–brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer’s disease. The amyloid β (Aβ) antibody mAb158 is radiolabelled and conjugated to a transferrin receptor antibody to enable receptor-mediated transcytosis across the BBB. PET imaging of two different mouse models with Aβ pathology clearly visualize Aβ in the brain. The PET signal increases with age and correlates closely with brain Aβ levels. Thus, we demonstrate that antibody-based PET ligands can be successfully used for brain imaging.
“Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease” by Dag Sehlin, Xiaotian T. Fang, Linda Cato, Gunnar Antoni, Lars Lannfelt and Stina Syvänen in Nature Communications. Published online February 19 2016 doi:10.1038/ncomms10759