Diagnosing dementia: Finding metabolites linked to Alzheimer’s disease

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  • Published: Oct 15, 2012
  • Author: Jon Evans
  • Channels: Electrophoresis
thumbnail image: Diagnosing dementia: Finding metabolites linked to Alzheimer’s disease

Forms of dementia

Diagnosing dementia: Finding metabolites linked to Alzheimer’s disease

Using capillary electrophoresis-mass spectrometry (CE-MS), Spanish and Swedish scientists have uncovered a suite of metabolite biomarkers that can not only accurately diagnose those with Alzheimer’s disease (AD), but can also diagnose those with milder forms of dementia.

These milder forms of dementia can progress to AD, but this is by no means a certainty. Indeed, the mildest form, known as subjective cognitive impairment (SCD) and characterized by self-diagnosed forgetfulness and occasional inability to find words, is often not dementia at all, but simply the normal consequences of ageing.

More serious is mild cognitive impairment (MCI), characterised by memory problems more severe than normal for a patient’s age and slightly impaired reasoning, although not enough to interfere with a patient’s day-to-day life. Studies show that those diagnosed with MCI do have a much higher risk of developing AD, but exactly how long this takes can vary widely and some never progress to AD.

Cerebrospinal fluid

Physicians are keen to find accurate ways to diagnose those with MCI and also to determine how likely they are to progress to AD. Current treatments can only really slow the progression of the dementia, meaning that it’s important to get patients on them as early as possible. By the time a patient has advanced AD, it is already too late.

Although brain scans and tests of mental ability can be used to diagnose dementia, they can’t determine whether this is due to AD. The only way to diagnose AD in living patients is to detect several AD-related proteins, particularly amyloid beta and tau, in their cerebrospinal fluid (CSF). But studies have shown that even this approach is not completely accurate and can struggle to identify those with early-stage forms of AD, including MCI.

This has spurred scientists to try to find other biomarkers in the CSF, such as suites of metabolites, that might be able to diagnose MCI and AD. So far, they’ve looked for these biomarkers using gas chromatography (GC) and liquid chromatography (LC) coupled with MS, but now for the first time a team led by Alejandro Cifuentes at the Institute of Industrial Fermentations (CSIC) in Madrid has used CE-MS.

They did this because they thought it might be useful to compare the metabolites detected by CE-MS with those detected by GC-MS and LC-MS, especially as CE-MS is better at detecting ionic and highly polar metabolites. Using CE-MS, they analyzed samples of CSF taken from 73 patients, some of whom had SCI, some of whom had MCI that remained stable over the next two years, some of whom had MCI that progressed to AD over the next two years, and some of whom had AD.

Classifying metabolites

Processing the subsequent spectral data with linear discriminant analysis (LDA) initially revealed 10 metabolites that could accurately distinguish between the different groups according to their concentrations. However, the SCI and MCI that didn’t progress to AD groups proved most difficult to distinguish, indicating that the two groups are biochemically very similar. So Cifuentes and his team combined these two groups into one, finding that the LDA now identified 14 metabolites that were able to distinguish between the groups even more accurately.

Testing these 14 metabolites on samples from 12 other patients split between the different groups, Cifuentes and his team were correctly able to classify 83% of the samples, making these metabolites more accurate biomarkers than the tau and amyloid beta proteins. Studying the 14 metabolites in more detail, Cifuentes found that many of them match those discovered by GC-MS and LC-MS, such as the nutrient choline and the amino acid valine. But others, such as the metabolite suberylglycine, had never been linked with AD before.

Cifuentes thinks that combining these 14 metabolites with the tau and beta amyloid proteins might produce a particularly effective method for diagnosing MCI and AD, and for identifying those likely to progress from one to the other. He is now looking to see whether similar predictive suites of metabolites can be found in more easily accessible bodily fluids, such as blood, urine and saliva.

Related Links

Analytical Chemistry (Article in Press): "Toward a predictive model of Alzheimer’s disease progression using capillary electrophoresis–mass spectrometry metabolomics"

Article by Jon Evans

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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