Jul 20, 2011

Studies Illuminate Possible Alzheimer's Biomarkers in Blood and Spinal Fluid

Early detection of Alzheimer's – even before outward memory and thinking symptoms are evident – is very important as the next generation of disease-modifying therapies are most likely to be effective if initiated during the earliest stages of the disease.

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Studies Illuminate Possible Alzheimer's Biomarkers in Blood and Spinal Fluid

It is believed that build-up of a toxic molecule known as beta amyloid in the brain of people with Alzheimer's occurs prior to cognitive decline. Thus, an accurate measurement or indicator of increased amyloid deposits in the brain could possibly provide an earlier diagnosis compared to current methods of cognitive testing, and also possibly indicate the severity or progression of the disease.

Two studies investigate new methods of early detection of Alzheimer's, tracking progression of the disease, identifying participants for research trials and measuring the impact of therapies. One study uses blood measurements for estimating the amount of a toxic substance known as beta amyloid deposited in the brain; the other study suggests that abnormal levels of certain proteins in cerebrospinal fluid (including beta amyloid) in people with mild cognitive impairment may indicate who will develop Alzheimer's within the next 10 years.

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Two Studies Illuminate Possible Alzheimer's Biomarkers in Blood and Spinal Fluid

Estimating Amyloid Build-up in the Brain Using Blood Measurements

One of the stated objectives of the Australian Imaging, Biomarker and Lifestyle (AIBL) study is to find a prognostic blood test for Alzheimer's, driven by the need for an early, cost effective and easily accessible screening test for the disease.

According to the AIBL scientists, an accurate indicator of increased levels of deposited amyloid in the brain holds the possibility for early detection of Alzheimer's. They state that PET scans for brain amyloid, although powerful and informative about deposits of amyloid in the brain, are not widely available and are considered too costly for widespread population screening. Thus, they are generally reserved for research purposes. Spinal fluid amyloid measurements have been shown to correlate with the amount of deposited amyloid in the brain; however, the procedure for obtaining spinal fluid is considered too invasive by some.

Samantha Burnham, PhD, CSIRO, Perth, Australia and colleagues in AIBL are working towards a more economic and accessible blood-based alternative. To this end, AIBL scientists have been monitoring, over time, the blood chemistry, cognitive ability and lifestyle factors of 768 healthy elderly people, 133 people with mild cognitive impairment (MCI) and 211 people with Alzheimer's. They have also performed genetic and neuroimaging testing on 288 of the study participants.

The researchers found that a small group of blood measurements, including amounts of certain proteins and hormones, correlated with the amount of deposited amyloid seen in the brain. More specifically, they generated a model using nine blood-based markers (including Aβ1-42, ApoE, and cortisol) to estimate the amount of deposited amyloid in the brain. With 83 percent sensitivity and 85 percent specificity, this estimate then determines if an individual has an abnormally high amount of amyloid deposited in the brain, indicating risk of Alzheimer's. The model was validated using a second cohort of 74 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For the ADNI validation study, measurements for two of the markers were unavailable; sensitivity and specificity of 76 percent were achieved.

"This model, if fully validated, may provide a means for assessing research outcomes for drug treatments and lifestyle intervention strategies," Burnham said. "It may also lead to an effective and economical screen that indicates if an individual is in the early stages of, or at risk of developing, Alzheimer's, and to justify further tests such as PET scans."

Measuring Amyloid in Cerebrospinal Fluid (CSF)

According to Henrik Zetterberg, MD, PhD, Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden and colleagues, previous studies have shown that the Alzheimer's-related abnormal proteins found in CSF – known as Abeta42, total-tau and phospho-tau – can accurate identify mild cognitive impairment (MCI) due to Alzheimer's up to 10 years before conversion to Alzheimer's dementia. However, they say, it remains unclear exactly when these biomarkers turn positive.

To investigate this question, the scientists performed lumbar puncture on 137 people with MCI and clinically followed them for more than nine years. During that time, 54 percent of the subjects developed Alzheimer's and 16 percent progressed to other forms of dementia.

The researchers found that:
  • Baseline CSF Aβ42 levels were reduced and T-tau and P-tau were elevated in patients who converted to Alzheimer's during follow-up period, as compared with non-converters (p< 0.0001). 
  • CSF Aβ42 levels were equally reduced at baseline in patients with MCI who converted to Alzheimer's within 0-5 years (early converters) compared with those who converted to Alzheimer's between 5-10 years (late converters). However, CSF T-tau and P-tau were significantly higher in the early converters compared with the late converters. 
  • A ratio of baseline Aβ42/P-tau predicted the development of AD within 9.2 years with a sensitivity of 88 percent, specificity of 90 percent, positive predictive value of 91 percent and negative predictive value of 86 percent. 

"In this study, we show that around 90 percent of MCI patients with pathological CSF biomarkers at baseline will develop Alzheimer's within nine to 10 years," Zetterberg said. "Our results suggest that the CSF biomarker profile is highly predictive."

"We also found that CSF Aβ42 seems to be an earlier biomarker than CSF tau proteins. High CSF tau protein levels indicate an intense neurodegenerative process and predict rapid progression to dementia. These biomarkers may be useful to select patients for early intervention in clinical trials, and to identify and monitor treatment effects," Zetterberg said.

Source Alzheimer's Association International Conference (AAIC)

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Original content Bob DeMarco, the Alzheimer's Reading Room