Focusing on a worldwide killer
Research Models
Regina Kelder

Focusing on a worldwide killer

Advances in imaging, a standout at this year's Society for Neuroscience meeting, have an important role to play in Alzheimer's disease.

Every four seconds a new case of dementia is reported somewhere in the world, and the global dementia caseload is expected to top 135 million by 2050, says Alzheimer's Disease International (ADI), a London-based group that represents 80 different Alzheimer's associations.

For the 44 million people living with Alzheimer's disease (AD) or other forms of dementia, not to mention the families who are shouldering the burden of caring for them, the impact of this looming public health epidemic is all too clear. People are desperate for solutions that can alleviate the memory loss and cognitive dysfunction, and they long for the day when science can provide therapeutic solutions, optimally drugs that significantly slow progression of the disease or, ideally, prevent it altogether.

Developing drugs that target the carnage playing out in brain cells is notoriously difficult, however, in part because this uniquely human disease is hard to diagnosis clinically and challenging to study in animals. It's no secret that one of the biggest hurdles drug developers have faced in finding compounds that actually work against AD is translating the results from mice to man. Mouse models typically develop amyloid plaques in their brains just as humans do, but because AD is uniquely human they do not develop Alzheimer's-like dementia, which is primarily why so many anti-amyloid strategies have failed to slow the disease in clinical trials.

Fortunately, the field is getting some lift from rapid advances in powerful neuroimaging tools that have allowed researchers to quantify deficits in CNS disease. This could enable the study of AD to advance in a more meaningful way and get us closer to more effective treatments.

With so much attention being showered on these new technologies, it's not surprising that neuroimaging seemed all the rage at the Society for Neuroscience (SfN) that runs through Nov. 19. There were numerous studies presented and lots of activity around the latest gadgets and applications showcased on the lively trade show floor.

In one study, Charles River scientists performed an extensive characterization of magnetic resonance imaging (MRI) on volumetric and Magnetic Resonance Spectroscopy (MRS) to quantify AD-like imaging readouts in a mouse model supplied by Merck. The model, called Tg4510, demonstrated significant and progressive declines in both cortical and hippocampal volume after 16 weeks of age, said Kimmo Lehtimäki, an MRI scientist at Charles River's Finland site who led the analysis and presented the findings at SfN on Sunday.

Unlike many of the transgenic mouse models that overexpress mutant familial AD amyloid precursor protein (APP) gene, the Tg4510 mouse model is designed to over-express human tau protein. In normal brains, tau stabilizes the tracks for intracellular traffic but in AD it becomes abnormally phosphorylated, forms clumps or tangles and is unable to keep the neurological trains running, so to speak.

Lehtimäki and colleagues used MRI and MRS to track changes in the brains of the Tg4510 mice and found imaging and spectroscopic characteristics in the mouse model similar to human AD. These included a decline in cortical and hippocampal volume—sites where phosphorylated tau tends to accumulate—and changes in brain metabolites thought to be biomarkers for AD. Specifically, the MRS found decreased levels of N-Acetylaspartate and glutamate and increased levels of myo-inositol by week 32.

While it is unclear why the deficits appeared much more rapidly in the Tg4510 model compared to other mouse models, Lehtimäki said the brain atrophy and metabolite changes suggest the model could be a "readily translatable tool" for studying new therapies for AD. "For many of the models now, it takes a long time to see changes in the brain pathology," says Lehtimäki.

The utility of proton MRS in evaluating the efficacy and safety of new drug candidates for AD and other CNS diseases figured in another poster presentation by Lehtimäki. The study, conducted in a variety of mouse models that mimic certain aspects of Huntington's disease, AD, cognitive decline, and amyotrophic lateral sclerosis (ALS), tracked changes in the levels of 17 different brain metabolites over progression of the phenotype.

Lehtimäki said the findings underscore the usefulness of MRS in examining CNS pathology in vivo in animals, which can go a long way in developing more effective therapeutics.