Authors: Alice Weatherston
Ruth Wood is an MRC Clinical Research Training Fellow (Neurology) researching spatial memory and Alzheimer’s disease with Professor John O’Keefe (University College London, UK) and Dr Dennis Chan (University of Cambridge, UK). During her previous NIHR Academic Clinical Fellowship with Dr Dennis Chan she was involved in the application of the Four Mountains Test (4MT) to Alzheimer’s disease patients. This test, originally developed by scientists at UCL, recently indicated high levels of accuracy for the assessment of Alzheimer’s disease, and could provide a reliable, cheap and simple diagnostic test. We talked to Ruth about the research she has been carrying out and the early hopes for the test.
You’ve been closely involved with the development and testing of the Four Mountains Test (4MT) for Alzheimer’s disease – what was the initial basis for the research?
The 4MT was developed by a group of researchers at UCL and was specifically designed to test the function of the hippocampus. There is extensive evidence that the hippocampus is critically involved in spatial memory. It was the discovery of ‘place cells’ in the hippocampus, and other spatially-related cells in nearby brain regions, that led to the award of the of 2014 Nobel Prize for Medicine or Physiology to Professors John O’Keefe , and Edvard and May-Britt Moser (Norwegian University of Science and Technology; Trondheim, Norway) “for their discovery of cells that constitute a positioning system within the brain”.
The team I work with, led by Dr Dennis Chan, wanted to apply the 4MT to patients with Alzheimer’s disease (AD), since the hippocampus is one of the first brain regions to show neurodegeneration in this condition. Patients with AD can develop subtle problems with their memory, in the form of mild cognitive impairment (MCI), before they develop dementia. However, on clinical grounds alone it can be very difficult to distinguish between MCI due to AD and other causes of memory impairment, such as anxiety. It is possible to do so using nuclear medicine scans or lumbar puncture based tests but these are expense, invasive and available only in a handful of tertiary centres. Given that up to 20% of the population over 65 years of age are considered to have MCI, there is an unmet need for alternative diagnostic strategies.
Given the early involvement of the hippocampus in AD, changes in spatial memory might be detectable at a very early stage of disease. We hypothesized that performance on the 4MT would predict which individuals with MCI would go on to develop Alzheimer’s dementia in the future.
How does the test work?
Participants are shown images of computer-generated landscapes. These can be shown in paper form or Powerpoint slides, though an iPad app version will soon be available. Each landscape contains four mountains arranged around the centre of the scene. The participant views a sample landscape for 8 seconds and then after a 2 second delay the landscape is presented again, but from a different viewpoint, alongside different landscapes also containing four mountains. The participant then has to select which landscape represents the same place they were previously shown. Fifteen landscapes are shown in total and in all this takes around 8–10 minutes to complete.
What have your results so far indicated?
We tested 15 patients with MCI and followed these individuals up over 2 years, during which time nine developed AD. The 4MT predicted which patients would develop AD with 93% accuracy. This level of accuracy was superior to that of MRI scanning and current best-in-class tests of memory and thinking.
It is important to note that, although very encouraging, the results of this study are only preliminary given our small sample size. However, our result is exciting because we have proved the concept that the 4MT could predict which patients with MCI will go on to develop AD.
Does this test work for all types of dementia?
One of the strengths of the 4MT is that it appears to be a relatively specific test for AD since other types of dementia do not affect the hippocampus to a similar extent in early disease. A study published in 2010 showed that the 4MT can be used to differentiate between patients with AD and those with frontotemporal degeneration.
What are the advantages of this technique over other currently utilized Alzheimer’s diagnosis or MCI tests?
The test most commonly used in memory clinics, The Mini Mental State Examination, does not effectively predict which individuals with MCI will go on to develop AD. Testing for biological markers of AD via lumbar puncture or PET brain scanning is expensive, invasive and very restricted in availability. In contrast, the 4MT is cheap, easy to administer and noninvasive.