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Imagers seek answers for Alzheimer's diagnosis


A parent with Alzheimer's disease dies, and her adult children, in their early 40s, discuss undergoing a genetic test to determine whether they carry a copy of the apolipoprotein E4 allele, a common Alzheimer's disease susceptibility gene. As worrisome as a positive test would be, these family members will at least have more certainty regarding Alzheimer's disease than the thousands of noncarriers who present to family practitioners each year with memory loss and impaired thinking.

A parent with Alzheimer's disease dies, and her adult children, in their early 40s, discuss undergoing a genetic test to determine whether they carry a copy of the apolipoprotein E4 allele, a common Alzheimer's disease susceptibility gene. As worrisome as a positive test would be, these family members will at least have more certainty regarding Alzheimer's disease than the thousands of noncarriers who present to family practitioners each year with memory loss and impaired thinking.

Often, a clinical diagnosis of AD comes too late for an individual to benefit from treatment. Clinicians can assign the diagnosis of mild cognitive impairment (MCI) to patients with memory complaints, but they cannot state emphatically which of these individuals will progress to AD. Typically, about 10% to 15% people diagnosed with MCI convert to AD within a year, while 30% to 40% do not convert, at least within a span of six to eight years.

"Patients, families, and even physicians are in a state of suspended animation. We don't know whether we should start treating for AD or tell the family to look into assisted living," said Dr. Norman L. Foster, a professor of neurology at the University of Michigan Medical School.

As people live longer, clinicians need clear markers that can identify earlier and more accurately those at risk of developing sporadic AD, which is different from and more prevalent than the familial type. Diagnostic imaging plays an increasingly crucial role in detecting AD, distinguishing it from other debilitating dementias, and monitoring the progress of drug therapy.

A range of imaging techniques have been developed that enable researchers to visualize different features of AD, notably volumetric changes measured with MR imaging and metabolic changes measured with PET and SPECT. While these techniques are sensitive to AD pathology, they lack specificity. Efforts are under way to combine these tests with biomarkers, such as protein and enzyme expression, and other imaging techniques, such as functional MRI and MR spectroscopy, to increase specificity.

In October, the National Institute on Aging announced the Alzheimer's Disease Neuroimaging Initiative (ADNI), a five-year, $60 million project that seeks to recruit 800 subjects to determine the best combination of imaging, biological markers, and clinical and neuropsychological assessments to detect MCI and AD. Imaging will include serial MRI, and the study will be the first setting for serial FDG-PET studies. In general, imaging is needed to address three outstanding clinical questions:

- How can mild forgetfulness caused by early, predementia AD be distinguished from mild forgetfulness caused by normal aging? This is a question of early detection.

- How can dementia caused by AD be distinguished from other dementing illnesses? This is a question of diagnostic specificity.

- What is the best way to test for drug efficacy? This question is important both for drug development and for following the course of approved drugs.


Many researchers consider histological imaging to be the future of dementia detection. This entails using novel radiotracers that bind to specific brain pathology associated with AD, such as amyloid plaques and neurofibrillary tangles. The "amyloid cascade" is a widely accepted theory postulating that the primary cause of AD is a series of events in the brain brought about by amyloid in various forms. A minority view holds that amyloid is simply a byproduct of other processes such as oxidative damage, inflammation, or cholesterol buildup.

Most drug companies are betting on the cascade theory, according to Chet Mathis, Ph.D., a professor of radiology and pharmaceutical sciences at the University of Pittsburgh. The university has licensed the technology for 2-(4¢-(methylamino)phenyl)-6-hydroxybenzothiazole, an agent known as Pittsburgh compound B, or PIB, to Amersham, which was recently purchased by GE Healthcare. GE intends to work with drug companies in using PIB, which binds to beta-amyloid plaques in the brain, to monitor anti-amyloid therapies in clinical trials. Mathis and PIB codeveloper Dr. William E. Klunk, an associate professor of psychiatry at Pittsburgh, are developing a fluorine-18-labeled analog of PIB that would give the tracer a two-hour half-life, making it more clinically practical than its current carbon-11 cousin, which has a 20-minute half-life.

Research has shown that PIB has a much greater retention rate in AD patients and those with MCI than in healthy controls. But an overlap between those with disease and normals leads to more questions, Klunk said at the International Conference on Alzheimer's Disease and Related Disorders (ICAD) in July.

"Are these false positives, or are they cognitively normal people with deposits of amyloid plaques? Does an initial deposit of amyloid eventually lead to AD? These are questions we are trying to answer," he said.

Investigators at the University of California, Los Angeles developed fluorine-18 dimethylamino-dicyano-naphthalene propene, or F-18 FDDNP, a PET tracer that binds to neurofibrillary tangles and beta-amyloid plaques. Initial results with FDDNP indicate a strong correlation between the PET signal and the degree of memory loss, according to Dr. Daniel H. Silverman, head of neuronuclear imaging at UCLA, who spoke at ICAD. Distribution volumes of FDDNP showed 15% to 40% increases, depending on disease progression, in AD patients versus age-matched controls. Areas of increased FDDNP uptake correlate inversely with FDG hypometabolic patterns. Furthermore, FDDNP binding was associated with decreased neuron density in the hippocampus of AD patients. Silverman echoed Mathis when he emphasized that the most promising use of histological imaging may be to evaluate and monitor the efficacy of anti-amyloid drugs.

Researchers at the Hospital of the University of Pennsylvania have developed 4-N-methylamino-4¢-hydroxystilbene, or SB-13, a C-11-labeled tracer that binds to beta-amyloid plaques. SB-13 showed results similar to PIB in a small study comparing the two tracers in six patients with AD and six healthy controls. These data have been presented at international conferences, said Dr. Daniel Skovronsky, a neuropathologist at Penn. The Penn team worked with researchers from the University of Toronto.

"It strengthens the case that both compounds are recognizing amyloid plaques," Skovronsky said.

Dr. Hank Kung and colleagues at Penn have also developed 6-iodo-2-(4¢-dimethylamino-)phenyl-imidazo[1,2]pyridine (IMPY), an iodine-123-labeled compound for SPECT imaging of beta-amyloid plaques. They have accumulated promising animal data and expect to have human data soon, which should indicate whether SPECT's low resolution is sufficient to reveal the burden of amyloid plaque, Skovronsky said. The researchers want to give the nearly five million patients with AD the option to have SPECT imaging, since it is more widely available than PET.


Researchers at the University of Arizona have been involved in detecting and tracking brain changes that precede the onset of memory and thinking problems in persons with the ApoE4 allele. They hope to use imaging to test promising primary prevention therapies-treatment before any symptoms-without having to study thousands of research volunteers or wait many years to determine whether or when they develop symptoms, according to Dr. Eric Reiman, clinical director of neurogenomics at the Translational Genomics Research Institute in Phoenix and associate head of psychiatry at the University of Arizona.

Reiman cites the Women's Health Initiative Memory Study, an ancillary study of the Women's Health Initiative, as an example of the "old-fashioned" type of study that takes many years and millions of dollars. The Women's Health Initiative study was halted in June 2002 because of evidence of increased risk of cardiovascular disease and breast cancer in women using combined estrogen and progestogen hormonal therapy. Preliminary results of the memory component, which used cognitive tests to gauge memory and thinking, revealed that women on HRT had an increased risk of developing dementia. The memory study included nearly 5000 women between the ages of 65 and 80 who agreed to participate in a 10-year placebo-controlled trial.

"What would have happened if investigators had used hormone replacement therapy as a primary prevention therapy soon after menopause? Such a study would require 50,000 subjects and take more than 20 years," Reiman said. "Most drug companies' patents would end before the study's conclusion."

This is where imaging comes in. The Arizona researchers have been longitudinally studying 200 people, average age 55, who have either two copies, one copy, or no copy of the ApoE4 gene. Every two years, participants undergo an MR scan, PET imaging, and a battery of memory tests. The researchers have already detected in asymptomatic carriers of the gene some of the same brain changes seen in patients with AD. They've noted a two-year decline in these measurements similar to those seen in patients with dementia. Based on these data, the investigators estimate that they would need 100 individuals over the course of two years to test a promising primary prevention therapy using imaging analysis rather than cognitive tests as the primary end point.

GlaxoSmithKline is one of the first drug companies to take advantage of Reiman's theories. The company has sponsored a one-year "proof of concept" study using FDG-PET to determine whether the drug Avandia, which is approved for type 2 diabetes, can slow the progression of AD. Imaging analysis, rather than cognitive testing, is the primary end pointing.

"With many more treatments coming online, it's not going to be possible to spend years and millions of dollars testing each one," Reiman said.


In unaffected subjects genetically at risk for early-onset AD, whole-brain atrophy measured with MR imaging has been shown to be predictive of decline to AD.

In a study yet to be published, Dr. Clifford R. Jack, a professor of diagnostic radiology at the Mayo Clinic in Rochester, MN, and colleagues compared normal elderly controls with patients with MCI by measuring hippocampal volume and the rate of change in the whole brain. The controls who converted to MCI had smaller volumes at baseline. The number of people who convert from normal to AD is typically small, about 1% a year. Thus, even though Jack's research shows specific and overall volume changes associated with MCI and AD, it is not specific for the disease. It becomes an engineering question, he said.

"We know the brain shrinks in patients with AD and also in people who are in the process of developing AD. But can we make precise measurements of that atrophy? If we can, then even very small changes can give us a diagnosis," Jack said.

One technique that promises to improve diagnostic specificity is arterial spin-labeled perfusion MRI. The procedure, which has been used in stroke treatment, can be performed in 10 minutes on a commercial scanner. The MR sequence inverts the polarity of water protons, which then flow into the region of interest and perfuse into extravascular space. The inverted protons, mixing with protons of a different polarity, are readily distinguished. Studies using this sequence in subjects with MCI and AD have demonstrated hypoperfusion similar to that seen in FDG-PET and HMPAO-SPECT studies.

Patients suspected of dementia will typically undergo a structural MR scan. They may then be referred for other imaging techniques such as SPECT or PET. An advantage of the arterial spin-labeled technique is that a patient can be given a structural MR scan and a perfusion scan at the same time, said Norbert Schuff, Ph.D., an associate professor of radiology at the San Francisco VA Medical Center.

MR spectroscopy also holds promise as a tool that can add specificity to a diagnosis of AD or MCI. Researchers have shown that patients with AD exhibit unique metabolite spectra. The most promising marker for differentiating normal healthy subjects from patients with MCI and AD is the ratio of myo-inositol (MI) over N-acetylaspartate (NAA). Many groups have consistently found that NAA, a marker unique to neuronal tissue, is reduced and MI is increased in AD patients. Several groups have also found reduced NAA and increased MI in those with MCI. The Mayo Clinic team found that MI is increased earlier than NAA is reduced. This finding could mean that MI is a more sensitive marker than NAA for early detection of MCI.

Performing MRS can be challenging, Schuff said, but newer automated programs will reduce the degree of operator expertise currently needed. Higher field scanners will also be more sensitive to some metabolites, increasing the value of MRS.

Blood oxygen level-dependent (BOLD) functional MRI may have a place in diagnosing MCI or AD and in determining the efficacy of treatment. Studies have shown that BOLD signal changes occur in the medial temporal lobe, as well as in other regions such as the visual cortex, in early-stage MCI. But BOLD imaging can be noisy. It is variable between patients and between scans of the same patient, mainly because subjects must always perform tasks such as finger tapping. Dr. Serge Rombouts, a researcher at the VU University Medical Center in the Netherlands, is trying to overcome these variables by using BOLD imaging during resting stage.

"It's very reproducible, like an EEG," he said.

Rombouts and colleagues have scanned a small number of healthy controls and have found that the networks that show BOLD activity during resting stage are the same networks, such as the visual cortex and the motor cortex, that show activation during different memory tasks. BOLD imaging has also recorded the effects of medication in subjects with MCI and AD.


In addition to greater throughput and better resolution, the advancement of PET technology has also meant more images per scan to interpret, sometimes up to 128. Several researchers are working with computer scientists to improve image analysis methods that will be clinically applicable. Foster and colleagues at the University of Michigan have demonstrated that looking at visual interpretation of stereotactic surface projection maps (SSPs) is preferable, more accurate, and more reliable than visual interpretation of transaxial images.

SSPs are a summary of an individual's pathology derived from multiple transaxial images. Other image analysis techniques summarize group data, averaging information across individuals for the entire brain. Foster's focus is simply on the cerebral cortex, the most relevant area for dementing illness such as AD. The ultimate goal is to make PET imaging data available to physicians at the time they are evaluating and treating patients, in real-time, Foster said.

A 1992 paper written by Dr. Philip Scheltens, a neurologist at the VU University Medical Center in the Netherlands, is receiving a great deal of attention today. The study details a way to roughly estimate hippocampal atrophy based on MR coronal slices. Scheltens has shown with several populations that visual assessment of atrophy has high accuracy for predicting who will convert.

"Despite the advancement of volumetric and whole-brain analysis techniques, which can take hours, this old-fashioned way is still relevant for diagnostic purposes and for predicting who will convert from MCI to AD," Scheltens said.

Visual assessment takes just a few seconds for an experienced rater. It's convenient for large clinical trials that can have hundreds of scans. Raters score the left and right side of the brain separately. Scores of zero and one are associated with normal; scores of two, three, and four are associated with disease. In a comparison study, visual analysis predicted disease better than volumetric analysis. Unlike volumetric analysis, visual assessment takes a global view of the hippocampal region, including medial temporal atrophy, which is probably more sensitive to AD in patients with MCI, he said.

Of course, volumetric analysis is fast becoming operator-independent. The future will be in those automatic methods, Scheltens said.


Much of the discussion about dementing illness may become moot in the future, as research reveals ways for people to avoid slipping into cognitive decline. Dr. Gary Small, a pioneer in FDG-PET imaging of AD at UCLA, has written his second book on memory health. The first, The Memory Bible, became a best seller. It billed itself as an innovative strategy for keeping the brain young and included stress reduction exercises, brain training, and tips on how to remember complicated information. His more recent book, The Memory Prescription, is garnering attention as well. In it, Small outlines a two-week program for brain health that includes diet, physical conditioning, and memory training.

Before appearing on a daytime talk show in California, Small performed fMRI on an employee. Her memory was good, but her brain was working very hard to retrieve facts. After completing the two-week healthy lifestyle regimen, she underwent another fMRI. This time, her memory score improved, and she used much less brain activity as well.

"It's the first time, I think, that pilot data came out on a daytime talk show," Small said.

Like many researchers, Small continues to search for new and better imaging techniques to unravel the mysteries of AD and other dementing illnesses. In the meantime, however, he hopes that people will take control of their health and prolong their cognitive abilities through simple lifestyle changes.

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