Clue to cause of Alzheimer's dementia found in brain samples

ScienceDaily (Oct. 22, 2012) — Researchers at Washington University School of Medicine in St. Louis have found a key difference in the brains of people with Alzheimer's disease and those who are cognitively normal but still have brain plaques that characterize this type of dementia.

"There is a very interesting group of people whose thinking and memory are normal, even late in life, yet their brains are full of amyloid beta plaques that appear to be identical to what's seen in Alzheimer's disease," says David L. Brody, MD, PhD, associate professor of neurology. "How this can occur is a tantalizing clinical question. It makes it clear that we don't understand exactly what causes dementia."

Hard plaques made of a protein called amyloid beta are always present in the brain of a person diagnosed with Alzheimer's disease, according to Brody. But the simple presence of plaques does not always result in impaired thinking and memory. In other words, the plaques are necessary -- but not sufficient -- to cause Alzheimer's dementia.

The new study, available online in Annals of Neurology, still implicates amyloid beta in causing Alzheimer's dementia, but not necessarily in the form of plaques. Instead, smaller molecules of amyloid beta dissolved in the brain fluid appear more closely correlated with whether a person develops symptoms of dementia. Called amyloid beta "oligomers," they contain more than a single molecule of amyloid beta but not so many that they form a plaque.

Oligomers floating in brain fluid have long been suspected to have a role in Alzheimer's disease. But they are difficult to measure. Most methods only detect their presence or absence, or very large quantities. Brody and his colleagues developed a sensitive method to count even small numbers of oligomers in brain fluid and used it to compare amounts in their samples.

The researchers examined samples of brain tissue and fluid from 33 deceased elderly subjects (ages 74 to 107). Ten subjects were normal -- no plaques and no dementia. Fourteen had plaques, but no dementia. And nine had a diagnosis of Alzheimer's disease -- both plaques and dementia.

They found that cognitively normal patients with plaques and Alzheimer's patients both had the same amount of plaque, but the Alzheimer's patients had much higher oligomer levels.

But even oligomer levels did not completely distinguish the two groups. For example, some people with plaques but without dementia still had oligomers, even in similar quantity to some patients with Alzheimer's disease. Where the two groups differed completely, according to Brody and his colleagues, was the ratio of oligomers to plaques. They measured more oligomers per plaque in patients with dementia, and fewer oligomers per plaque in the samples from cognitively normal people.

In people with plaques but no dementia, Brody speculates that the plaques could serve as a buffer, binding with free oligomers and keeping them tied down. And in dementia, perhaps the plaques have exceeded their capacity to capture the oligomers, leaving them free to float in the brain's fluid, where they can damage or interfere with neurons.

Brody cautions that, due to the difficulty in getting samples, oligomer levels have never been measured in living people. Therefore, it's possible these floating clumps of amyloid beta only form after death. Even so, he says, there is still a clear difference between the two groups.

"The plaques and oligomers appear to be in some kind of equilibrium," Brody says. "What happens to shift the relationship between the oligomers and plaques? Like much Alzheimer's research, this study raises more questions than it answers. But it's an important next piece of the puzzle."

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The above story is reprinted from materials provided by Washington University in St. Louis. The original article was written by Julia Evangelou Strait.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL. Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Annals of Neurology, Sept. 1, 2012

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Use of anti-psychotic drugs by people with dementia 'under reported'

ScienceDaily (Oct. 17, 2012) — The scale of the challenge to reduce the use of anti-psychotic drugs by people with dementia may be under-estimated, according to researchers from Aston University and the University of East Anglia, working with NHS Kent and Medway. There is a key public health challenge to reduce the prescribing of anti-psychotic drugs to people with dementia as they are thought to be associated with up to 1,800 deaths a year.

Ian Maidment, corresponding author and a Senior Lecturer in Clinical Pharmacy from Aston University has worked in medication management in dementia for 20 years states: 'The true scale of anti-psychotic usage in dementia may be under-estimated. Usage may be up to 46% greater than official figures suggest.'

The researchers compared the results of the government's National Dementia and Anti-Psychotic Prescribing Audit with research, led by Anne Child, an experienced senior clinical pharmacist for NHS Kent and Medway cluster of primary care trusts (PCTs). They found that 15.3% of people with dementia received an anti-psychotic, compared to the national audit, which found 10.5%. However, only 48.9 per cent of GP practices across the country participated in the national audit compared with 98.3 per cent of practices in Medway which took part in the detailed local study.

The Medway project, carried out from January to December 2011, and analysed by researchers from Aston University and the University of East Anglia, identified that

·People with dementia living in care homes were nearly 3.5 times more likely to receive a low-dose anti-psychotic than people living at home (25.5 per cent compared to 7.3 per cent)

· It was possible to reduce or withdraw low-dose anti-psychotics for more than 60 per cent of patients with dementia (43 out of 70) whose medication was initiated by their GP.

· Clinical trials need to be commissioned as a matter of urgency to confirm the effectiveness of pharmacist medication reviews.

The paper, which appears in the BioMed Central's open access journal BMC Psychiatry, also sets out the detailed process undertaken before and during withdrawal of anti-psychotics from patients.

Anne Child, primary author, who is now Head of Pharmaceutical Care at Avante Care and Support said: 'We have demonstrated that a multi-disciplinary approach to dementia care, involving a pharmacy-led medication review, GPs, and care homes, can produce a positive outcome for patients, in one region of the country. More work is now needed.'

Dr Chris Fox, co-author, from UEA's Norwich Medical School said: 'Another issue with the national audit is it fails to report the usage of the drug lorazepam, which is sometimes used instead of anti-psychotics. It is potentially equally dangerous. Until we capture the true level of usage of all these drugs we cannot truly understand the issue.'

Ian Maidment added: 'Whilst the national audit is an important first step, it presents a partial picture. If we rely on it, exclusively we are doing a disservice to people with dementia, their carers and their families.'

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The above story is reprinted from materials provided by Aston University.

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Journal Reference:

Anne Child, Amy Clarke, Chris Fox, Ian Maidment. A pharmacy led program to review anti-psychotic prescribing for people with dementia. BMC Psychiatry, 2012; 12 (1): 155 DOI: 10.1186/1471-244X-12-155

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