This is lay information for the ‘All-in-One’ study, funded by the Alzheimer's Society. Aspects of the research plan have been updated to keep up with scientific advances made during the pandemic, to ensure the research remains relevant to the future of the NHS. The study will use blood samples, advanced MRI imaging and cognitive assessment in an All-in-One package to diagnose Alzheimer's disease and aid the prediction of progression.
What is Mild Cognitive Impairment (MCI)?
Between 5 and 20% of people over 60 experience mild cognitive impairment (MCI). MCI is defined as: decline over time in at least one cognitive area (e.g., memory, language, spatial orientation, or forward planning) that is confirmed by pen-and-paper testing. Patients with MCI do not have dementia – they are independent in activities of daily living - but often have the underlying diseases associated with dementia, like Alzheimer disease or damage to the blood vessels supplying the brain cells (neurons). Alzheimer disease is associated with deposits of Amyloid and Tau. Amyloid is a protein which builds up outside neurons before they begin to die but also accumulates with normal ageing. However, Tau builds up inside neurons only during certain disease processes, inevitably leading to cell death.
Does MCI lead to dementia?
People with MCI are at increased risk for developing dementia in the next two years. However, not all patients with MCI will ultimately develop dementia and in those who do, progression of symptoms is often very slow. Dementia will sometimes only develop after 5 or 10 years. This causes huge uncertainty for future planning, often resulting in a feeling of disempowerment for patients, relatives and doctors.
How do we predict who will decline?
There are multiple diagnostic techniques that can provide more certainty. These include scanning by magnetic resonance imaging (MRI) or positron emission tomography (PET) and lumbar puncture to examine cerebrospinal fluid (CSF). Using these techniques, research has shown that there are two specific biological markers that allow better prediction of progression from MCI to dementia within the next few years. The presence of high levels of Tau and altered levels of Amyloid, either on scans or in the CSF, can predict progression quite accurately. However, many barriers exist to the uptake of these diagnostic techniques.
PET scans are expensive (£1600), and not available for Alzheimer’s disease in the NHS. Analysis of CSF requires 1) the clinical skills to safely perform a lumbar puncture, and 2) specialised laboratories for sample processing. CSF analysis is currently being performed at only one or two laboratories nationally. People with MCI are often reluctant to have a lumbar puncture because of its perceived “riskiness” or “painfulness”. Even though that is no longer true, this has led to low uptake. Further, lumbar puncture can be complicated in those on certain medications, for example blood-thinners.
What has changed?
Between 2019 and 2022 there has been a quiet scientific revolution in the analysis of blood for markers of AD and other diseases. Fifteen years of work by investigators like our collaborator, Prof. Henrik Zetterberg, have come to fruition. It is now possible to use an ordinary blood sample to estimate the amount of various proteins in the brain, and therefore the amount of injury to neurons. This helps estimate the risk of progression to dementia in people with MCI. Therefore, for NHS patients there is an urgent clinical need to examine how we can use currently available diagnostic tools: pen-and-paper tests, inexpensive MRI scans and clinical history, alongside these new blood markers, in order to make better predictions for people with the earliest stages of cognitive decline.
What do we want to do?
We aim to test the real-world usefulness and acceptability (to patients and clinicians) of a package of diagnostic tests in people with mild cognitive impairment. Our objective is to prove that such a package can be used across the NHS. We will examine whether it would be cost effective for the NHS to roll this out across memory assessment services nationally, and whether we can even further reduce the MRI scanning duration to make the experience even easier for people with MCI.
The scientific developments in blood-based biomarkers have meant we are now pursuing up-to-date, cost effective tests which avoid the bottlenecks created in the NHS by the COVID19 pandemic. We therefore propose a study using high resolution MRI scanners in Manchester and Cambridge to demonstrate the clinical feasibility of a novel “All-in-One” diagnostic package. This will use combined blood markers, pen and paper tests and MRI scans to deliver standardised, blood-based estimates of brain Amyloid and Tau deposition and neuronal damage in MCI. Previous research studies often excluded patients with significant vascular risk factors, such as hypertension and diabetes, which are common in patients with MCI. These factors are also associated with dementia risk. We will examine whether comprehensive All-in-One assessment, including assessment of neuronal damage due to vascular causes, can deliver the same or better accuracy when predicting who goes on to develop dementia.
Is PET scanning still useful?
PET scans use a radioactive tracer which sticks to harmful proteins in the brain. PET scans still represent the gold standard for the diagnosis of Alzheimer disease in the brain during life. However, in the last 3 years much more research has focused on using PET markers sensitive to Tau, the protein inside brain cells, rather than Amyloid which coats the outside. This is because Tau is 1) more specific to Alzheimer’s disease, 2) does not increase in normal ageing and 3) is a better predictor of cognitive decline. However, PET scans remain extremely expensive, and Tau tracers do not currently have a clinical license in the UK. Tracer supply is precarious and relies on a just-in-time supply chain with expensive tracers, sometimes supplied from abroad. While PET scanning remains an important research tool, over the last 3 years it has become much less likely that it will be used in routine AD diagnosis in the future. The backlog in cancer diagnoses requiring PET scans which has been caused by COVID19 is also likely to make this investigation much less available.
Is MRI scanning still useful?
We still use MRI scans to examine the structure of the brain [see figure 1]. This remains important because of the high rate of cognitive problems caused by cerebrovascular disease which is only evident on MRI. MRI can provide us with measures of the volume of different segments of the brain, and how well the brain areas are connected, a technique called “diffusion imaging”. MRI scanners are widely available, which means that for the foreseeable future MRI scans will be a routine part of clinical diagnosis, especially at the earliest stages of disease. One of our aims is to use the high-quality information we will get from blood markers to develop new techniques in MRI scanning and image analysis. This will help make the best use of this already-existing, widespread, (and relatively cheap) technology. More recent advances in MRI technology like Arterial Spin Labelling (ASL) can tell us about the brain’s blood flow, and may be able to mimic some of the aspects of FDG PET scans. Arterial Spin Labelling [see figure 2] tracks the water in the blood as it circulates in the brain by briefly magnetising it first. An image is then captured after a few microseconds. This image is subtracted from a background image to measure brain blood flow.