Alzheimer’s – early diagnosis vital

There are currently an estimated 700,0001 people in the UK with dementia – a figure that is predicted to double within a generation, yet a report by the National Audit Office (NAO) reveals that dementia is being given too low a priority by health and social services. The report said that the UK performance is in the bottom third of Europe, below almost all northern and western European nations – with the average time taken to diagnose patients being twice as long when compared to some other countries.2

Many healthcare professionals are failing to recognise the importance of early diagnosis – fewer than two thirds of GPs surveyed believed it was important to look actively for early symptoms. Although the Department of Health says that early diagnosis and intervention in dementia is cost-effective, there is a significant diagnosis gap and less than a third of people with the disease ever receive a formal diagnosis.

Speaking to The Clinical Services Journal, Rebecca Wood, CEO of the Alzheimer’s Research Trust (ART), commented: “One of the problems has been that clinicians have been slow in recognising dementia as a true disease (or rather a range of diseases). The attitude has been ‘what do you expect at your age?’ It hasn’t been viewed as an illness worth diagnosing, that you can do something about.”

The NAO draws parallels between dementia now and cancer in the 1950s, when there were few treatments and patients were commonly not told the diagnosis for fear of distress. However, there are significant benefits to early diagnosis.

“The reason that early diagnosis is important, even though we do not have a definitive treatment for dementia at present, is to exclude other forms of illness including depression. In the very early stages of dementia, these are often confused with each other. A formof Vitamin B deficiency also mimics dementia and is reversible,” said Rebecca Wood.

Likewise, this is the case for thyroid hormone deficiency. It is therefore important that all patients with dementia are diagnosed and screened for these treatable causes very early on.

“It is also essential to tell the difference between the different types of dementia, because they require different treatment methods. However, it becomes harder to distinguish between forms of dementia in the more advanced stages, which is another reason for early diagnosis,” she pointed out.

She added that early diagnosis allows individuals to make decisions about their life while they are still able. It gives them longer to get used the idea that they have the disease and also for their family to come to terms with the illness.

Being treated early gives patients more self-confidence she continued: “Selfconfidence is an important aspect of dealing with the disease, allowing patients to go on for longer and prolonging their ability to do things for themselves. They feel that something is being done, which can have a significant effect. This is particularly important as people are able to stay in their own homes for longer, and we know that patients are better able to cope in familiar surroundings. Moving to a new and strange environment can have a detrimental effect on their condition.”

BREAKTHROUGHS

The NAO says that brain scanning (MRI or CT) is currently recommended to establish a clear diagnosis although it is only used regularly by 66% of community mental health teams.2

However, researchers are constantly seeking ways to improve early diagnosis and there are hopes for simpler, more costeffective methods on the horizon.

Investigations are underway into blood or urine tests, the identification of genetic and protein biological markers and more accurate psychological tests. Rebecca Wood pointed out some exciting breakthroughs. “PET and MRI imaging are getting better all the time and hopefully, in the future, the cost will come down. Imaging is an expensive form of diagnosis, but a potential new blood test is looking very promising. “Overseas, spinal taps are carried out, but in the UK this is regarded with some distaste. It is an uncomfortable procedure and, with a patient with more advanced dementia, it can be particularly distressing and problematic. We are hoping, in the future there will be more a simple blood test available that can be carried out by a GP.”

ART is funding work in this area and the use of proteomics has discovered two proteins identified in blood samples which are confirmed to be markers for the disease. This discovery is the result of blood tests carried out on 500 Alzheimer’s patients, as part of a five-year project based at the Institute of Psychiatry, King’s College London. The findings take researchers a step closer to knowing whether a blood test can be used to diagnose and measure progression of the disease.3

Other research into non-invasive forms of diagnosis has produced a simple urine test to measure the level of a brain protein called neural thread protein (NTP), known to be elevated in patients with Alzheimer’s.3

PSYCHOLOGICAL TESTING

Psychological testing is also looking very promising according to Rebecca Wood. A study is underway into how to differentiate between different types of dementia, based on the paired associative learning system. This focuses on the recognition of famous faces and spatial awareness, for example, and helps diagnose different types of dementia such as semantic dementia (SD) and Alzheimer’s disease (AD).3

Researchers believe that the new tests will help to supplement the existing written memory tests typically used to diagnose AD. In the study, co-funded by ART and the Medical Research Council (MRC), researchers asked people with AD and SD to identify the ‘odd-one-out’ from a series of faces and scenes. They found that people with AD had difficulty with scenes, while those with SD scored poorly on the facial tests. The findings support previous research by the team suggesting that different areas of the Medial Temporal Lobe region of the brain, damaged in dementia, may be responsible for different aspects of memory and perception.

Professor Kim Graham from the School of Psychology, Cardiff, said the study could lead to the production of simple clinical tests that enable doctors to diagnose and screen for specific forms of dementia. Prof Kim Graham, said: “We’ve known for many years that damage to the Medial Temporal Lobe results in poor long term memory. The study suggests that damage to this brain region also affects perception of simple face and scene stimuli, with unique profiles of performance seen in different dementias.”

With semantic dementia, patients lose their store of factual knowledge about the world, including words, concepts and people. However, day-to-day and spatial memory is typically unaffected. The researchers found that people with SD did well at the scene tasks and did not experience the episodic memory and amnesia associated with AD.

“Some people with Alzheimer’s have difficulty with words at the early onset of the illness. It can be very difficult to tell the difference between semantic dementia and Alzheimer’s disease at this stage,” Rebecca Wood commented. “As drugs are developed, distinguishing between these conditions is going to become increasingly important. It won’t be enough to simply diagnose dementia.”

According to Prof Graham, people with Alzheimer’s show difficulty with navigation and recalling scenes, so the test asks the individual to look at scenes of landscapes, then identify the one’s they have seen before, after a delay. Those with early AD found it virtually impossible to recall the scenes, but did not have difficulty memorising faces. In the later stages of AD, the ability to recollect faces deteriorates, providing a marker for the disease’s progression.

The second part of the test, shows four scenes and the patient is asked to spot the “odd one out”. Those with early stage AD find it difficult to discriminate between these images – indicating this is not simply a problem relating to memory but to spatial cognition. In fact, brain scans on patients with early AD show the areas tasked with navigational tasks are atrophied. Both the tests are very sensitive, Prof Graham reported.

She told The Clinical Services Journal: “The next step will be to perform the tests on a broader, heterogenous clinical sample and combine these cognitive markers with other pathological markers believed to be sensitive to early AD, such as blood tests or protein biomarkers.”

BRAIN SCANNING

Brain scanning and EEG technology are also making steps forward. In the US, there has been promising research at Rowan University, Glassboro, N.J, the University of Pennsylvania School of Medicine and Drexel University which may lead to improved early diagnosis.4

The study found that early Alzheimer’s could be diagnosed with a high rate of accuracy through evaluating electroencephalogram (EEG) signals. The researchers employed signal processing and automated neural network analysis of event related potentials (ERPs) of the EEG signals, monitoring how the patients’ brains reacted to a series of auditory stimuli. Patients were asked to respond by pressing a button every time they heard a high frequency tone, known as the “oddball” tone, which generates ERPs in the EEG. Generally, in the ERP of a person without Alzheimer’s, that response registers a peak, the P300, about 300 milliseconds after the “oddball” tone. People with dementia, particularly Alzheimer’s, may exhibit that peak much later than 300 milliseconds, show a much weaker peak or have no peak at all. The teams conducted several experiments, ultimately evaluating the parietal and occipital regions of the brains of 71 individuals. Their diagnostic accuracy rate was 82% to 85% using the EEGs. The team members hope that eventually a hand-held device will be developed that can be used to conduct evaluations.

American scientists tracking the loss of key nerve cell receptors in early Alzheimer’s also have raised hopes that new brain scan techniques being used in their research could speed up diagnosis. Scientists at UCLA developed a method of tracking the loss of key receptors in brain tissue caused by the earliest stages of AD.3 The research used PET scanning and a chemical called MPPF to see what was happening inside the brains of people affected by Alzheimer’s. They measured the amount of “serotonin receptors 1A” in nerve cells in an area of the brain affected in the early stages of the disease.

Rebecca Wood said: “This is an interesting, though very small preliminary study. MPPF was first proposed as a chemical marker of serotonin 1A receptors in the brain in 1997 and since then it has been shown that it is indeed a good marker of these receptors. The study of these receptors is particularly important for Alzheimer’s research, since the most vulnerable neurons in the hippocampus – one of the most vulnerable regions in Alzheimer’s – contain a high density of these receptors. The loss of neurons in the hippocampus is also measure of the severity of the disease.

‘’The scientists showed that there was some receptor loss in people with mild cognitive impairment, which is regarded as a pre-clinical stage of Alzheimer’s in some people. This could mean that loss of these receptors is a very early marker of Alzheimer’s.”

The authors made other useful correlations, for example between loss of the serotonin 1A receptors and decline in score on cognitive test, and between receptor loss and decline in glucose utilisation in the brain.

Rebecca Wood said there is still a lot of work to be done before this promising method can be widely used, but these results could help scientists to better understand how the disease progresses and develop new methods of early diagnosis. When new treatments are being tried in the future, these scanning techniques could also help to assess if any new drugs are having an effect.

Researchers have also published results on a luminous dye that, with further work, could shed light on a new way to diagnose AD. A chemical is used that binds to areas in the brain damaged by the disease and gives off a fluorescent glow that can be picked up by a brain scan.3

ART explained that this may provide a possible method for optical imaging of the amyloid plaques that build up in the brains of people before they have full Alzheimer’s. There is still some way to go before this could work as a fully non-invasive diagnostic technique and scientists also need to investigate any possible toxic effects. However, if this further work is successful this could lead to a fairly simple and practical way of detecting the plaques in the early stages of Alzheimer’s.

BIOMARKERS

Other biomarkers are under investigation. New research, funded in part by ART, has identified a potential early marker for disease progression through increased changes in a protein, CRMP2, in the brains of Alzheimer’s patients. Importantly, they found that it occurred before any plaque and tangle formation in the brain, the two hallmarks of Alzheimer’s.3

A falling total level of cholesterol could also be an indication of early dementia. Researchers led by Robert Stewart of King’s College London monitored the level of cholesterol in a group of men over a period of 26 years. 56 of these men had dementia and 971 did not. The researchers observed that the level of cholesterol had diminished at least 15 years before the diagnosis and remained at low levels throughout the whole period. They suggest that it is therefore possible that a drop in the level of cholesterol could be associated with the early stage in the development of dementia.5

Gene research has also produced some interesting findings. Research was carried out in Canada and the United States, involving DNA samples from 6,000 people, and examined variations of the SORL 1 gene. One particular variation was found to be more common in people with late onset AD.6

SORL 1 is a gene that plays an important role in preventing amyloid precursor protein (APP) from being transformed into a toxic byproduct, which in turn contributes to the build up of amyloid plaques in the brain. Abnormalities and a deficiency in this gene have recently been linked to the development of late onset Alzheimer’s disease (AD).

In addition, another gene linked with late-onset Alzheimer’s has been discovered called GAB2.3 People with a damaged copy of the gene are believed to be four times as likely to develop dementia. In time, it may be possible to identify those most at risk and offer preventative treatment. Significant steps forward are already being made that could lead to the “holy grail of a vaccine”, according to Rebecca Wood.

VACCINE

“The manufacturers of a vaccine called CAD106 say it has stopped amyloid build up in the brains of mice bred to mimic some of the symptoms of Alzheimer’s. Their researchers are now testing the drug in a small number of people to check whether it is safe. If successful, they will study the effect of the drug in larger numbers of people.”

The first anti-Alzheimer’s vaccine tested on humans – AN1792 – worked in a similar way, but trials were stopped after a few patients developed harmful side-effects. Different versions of the vaccine are still being studied and ART believes this shows significant potential. In addition, the new CAD106 vaccine does not stimulate the same immune response as the original vaccine, which could mean fewer sideeffects. Rebecca Wood added: “It is too early to say whether this will lead to a treatment for Alzheimer’s and a lot more research is needed to see whether the drug is safe and works. The interesting aspect of the original vaccine was the fact that it was clearing plaques. But we don’t know, just yet, whether this will affect cognition. In addition, the brain does need some amyloid.”

She says that any vaccine programme would need to be very targeted. As it would be expensive to have a blanket vaccination plan, a cost-effective test to establish who is at most at risk would be a key factor.

“At the moment we do not have a clear-cut genetic picture. Early diagnosis would allow us to determine who would benefit most from a vaccine,” Rebecca Wood explained. “It is also important for looking at ways of measuring the progress of the disease. Biomarkers could be used to measure the progress of the disease and therefore whether treatment is having any effect.”

Once the diagnosis is made, it is important to administer drugs as early as possible, she said: “Unfortunately, because of the NICE guidelines, this is very difficult in the very mild stages. New evidence suggests that the current drugs available may have an effect on the underlying causes of the disease, rather that just alleviating the symptoms. It may affect the course of the disease, which supports the case for early diagnosis and treatment.”

Combinations of imaging strategies with genetic, clinical and cognitive assessments will be key to identifying people at high risk of developing Alzheimer’s. In the meantime, the Government has recognised the inadequacies of the present system. Health Minister Ivan Lewis said he is “determined that this disease is brought out of the shadows” and has announced that the Government will produce the first national dementia strategy. It will take 12 months to complete, but early diagnosis will be a key focus he revealed.

REFERENCES

1 Figures from the Alzheimer’s Research Trust: www.alzheimers-research.org.uk

2 NAO Report: Improving service and support for people with dementia (4 July 2007). To download full report, visit: www.nao.org.uk

3 Alzheimer’s Research Trust’s news archives: www.alzheimersresearch. org.uk/news

4 Medical News Today, 18 April 2007, www.medicalnewstoday.com

5 Stewart, R. White, L. R. et al. (2007), Twenty-six years change in total cholesterol levels and incident dementia: the Honolulu-Asia aging study, Arch Neurol. 64 (1): 103-107

6 Dunham, W. (2007), New gene linked to Alzheimer’s identified, Reuters: www.today.reuters.com

FURTHER READING
• 2007 Dementia UK report, Alzheimer’s Society.