Diagnosing Mild Cognitive Impairment

Summarized by Robert W. Griffith, MD
May 3, 2007

Summary

A new type of PET scan using FDDNP (a molecule that binds to plaques and tangles in vitro) has been developed. It displays the plaques and tangles of Alzheimer's disease and, to a lesser degree, those seen in mild cognitive impairment (MCI), and is superior to glucose-PET and MRI for diagnosis of both conditions.

Introduction

As people get older, they find themselves worrying if their minor memory lapses represent the early stages of Alzheimer's disease. In recent years, physicians have refined their views on the condition known as mild cognitive impairment (MCI), which can be seen as a transitional stage between normal aging and Alzheimer's. MCI is reported in 19% among people under 75, and in 29% of people under 85. And among those who have it, roughly 12% progress to Alzheimer's disease each year, so that after 6 years about 80% of them have Alzheimer's.

The brain pathology of Alzheimer's consists of accumulations of microscopic plaques of debris containing beta-amyloid, and tangles of nerve endings containing a protein called tau. These changes have also been detected in some parts of the brain in mild cognitive impairment. Until now, it's only been possible to detect plaques and tangles in tissue obtained at autopsy, but a recent publication in the New England Journal of Medicine describes a radiographic technique to display them; this is a summary of the report.

What was done

Volunteers with self-reported memory problems aged between 49 and 84 were found through advertisements and referrals from physicians. After exclusions because of illness, certain medications, or insufficient interest, there were 108 who completed the initial tests and were enrolled in the study. A further 25 were eliminated because of conditions uncovered by the actual test procedures (psychiatric evaluation and the PET scan), such as Lewy body dementia, traumatic head injury, depression, substance abuse, and brain tumor.

The psychiatric exam included the Mini-Mental State Exam (MMSE), the Hamilton Depression Rating Scale, and a battery of tests for cognitive problems, including memory tests. Standard criteria were used to diagnose MCI and Alzheimer's disease.

A PET scan¹ was done on all participants, using FDDNP, a molecule that binds to plaques and tangles in test-tube studies. The degree of FDDNP binding was determined in scans obtained over a 2-hour period, and quantified. A second PET scan was done within 2 weeks, using FDG, a glucose metabolism indicator, to allow evaluation of the rate of tissue metabolism. Finally, 72 of the 83 participants had a brain MRI, which was used to give detailed anatomical information.²

What was found

Based on cognitive testing, 25 of the 83 subjects were classified as having Alzheimer's disease, 28 as having MCI, and 30 as healthy controls (their memory complaints were found to be 'normal aging'). The controls were significantly younger than the MIC or Alzheimer's group subjects, but otherwise the three groups were similar regarding gender distribution, years of education, and family history of dementia.

The MMSE scores averaged 29.3 for controls, 27.2 for the MCI subjects, and19.9 for the Alzheimer subjects. Other cognitive tests showed similar results.

The average values for FDDNP binding on PET scans differed significantly between the three groups. They were lower in the control group than in those with MCI, and lower in the MCI subjects than in those with Alzheimer's.

FDG-PET metabolism scores and MRI-derived volumes of two areas of the brain were higher in the controls, mid-way in the MCI group, and lowest in the Alzheimer's subjects. However, the FDDNP binding differentiated between the groups better than either the FDG-PET or MRI results.

What the results mean

This study shows that FDDNP-PET scanning can differentiate people with mild cognitive impairment from those with Alzheimer's disease on the one hand, and those with normal brain function on the other. It's superior to another PET scan (FDG's glucose metabolism) and MRI volume estimates.

Several treatments in development for Alzheimer's are targeted at preventing the formation of plaques and tangles, or dissolving them once formed. This means that a non-invasive method of determining their presence, such as the FDDNP-PET scan, would allow very early diagnosis of Alzheimer's, or even of mild cognitive impairment. Treatment could thus be started at an earlier stage than at present, and its effectiveness in reversing the pathology might be assessed. At the very least, the FDDNP technology will prove useful in developing proxy tests for the presence of plaques and tangles - e.g. something similar to beta-amyloid blood levels, but much more specific.

Source

• PET of brain amyloid and tau in mild cognitive impairment GW. Small, V. Kepe, LM. Ercoli,  et al. , N Engl J Med, 2006, vol. 355, pp. 2652--2663

Footnotes
1. A positron emission tomography (PET) scan is a type of imaging test that shows how the tissues and organs are functioning. Unlike other scanning techniques, a PET scan doesn't produce clear structural images. Instead, it shows images with areas of more or less intense color, which provide information on the chemical activity within the tissues. This chemical activity varies with the chemical injected in conjunction with the scan.
2. Magnetic resonance imaging (MRI) uses radiofrequency waves and a strong magnetic field rather than x-rays to provide remarkably clear and detailed pictures of internal organs and tissues. MRI requires allows evaluation of some body structures that may not be as visible with other imaging methods. Because the strong magnetic field used pulls on any magnetic metal object implanted in the body, people with an artificial hip, heart pacemaker, or any metal plates, pins, or screws cannot have an MRI.

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