Exploring All Possibilities to Improve AD Diagnosis

AD pathology begins to develop long before clinical symptoms are readily apparent. However, AD diagnosis currently depends on assessing a range of cognitive and behavioral changes over time. Finding a way to detect the disease at the earliest point possible will allow clinicians to treat it as early as possible. One active area of AD research focuses on the development of sensitive screening instruments and neuropsychological tests to diagnose cognitive decline, aMCI, and AD as early as possible.

Ambitious efforts also are underway to find new ways to measure changes in the structure and function of the brain and in other biomarkers, such as substances in cerebrospinal fluid (CSF), and blood. These biomarkers may hint at pathological changes that occur before clinical signs of aMCI or AD are evident or when they emerge. Improvements in brain imaging and new findings about CSF biomarkers are already yielding results. For example, the development of PiB has enabled scientists to visualize beta-amyloid plaques in the living brain. Advances like this may lead to very early diagnosis of AD and will help researchers and clinicians develop new treatments and monitor their effectiveness.

• Clinicians need practical tools to help them differentiate memory and thinking changes that come with normal aging from those of very mild dementia. Existing cognitive tests may not be sensitive enough to detect problems in highly educated individuals or may falsely identify people with poor lifelong cognitive functioning as demented. Other tests are not practical for general clinical use.
  
  Investigators at the Washington University School of Medicine developed a new tool, the AD8, which takes advantage of the knowledge that family and close friends have of a person with memory or cognitive problems. The AD8 asks about changes in the way a person remembers or acts in various circumstances, such as forgetting appointments or having difficulty handling financial affairs. Since the AD8 was published in 2005, two studies (Galvin et al., 2006; Galvin et al., 2007) have demonstrated its reliability, validity, and flexibility. The tool can be used in face-to-face encounters or over the phone, and it can even be completed by a person with memory problems. These studies suggest that a tool like the AD8 could improve dementia diagnoses in primary care, where dementia often goes undetected. This tool also may be valuable in screening for clinical trials, community surveys, and epidemiologic studies.

• Because AD is a progressive disease, investigators want to be able to predict the progression from normal cognition to aMCI to AD. Two studies used neuropsychological tests to explore this area. The first study, by scientists at Harvard Medical School, indicated that the risk of progressing from normal cognition to aMCI was greater in individuals with relatively low scores on tests of episodic memory, and that the risk of progressing from aMCI to AD was increased in people with relatively low scores on tests of both episodic memory and executive function (Blacker et al., 2007). In the second study, conducted within the Alzheimer’s Disease Cooperative Study (ADCS), investigators found that the best predictor of progression from aMCI to AD over the 36-month trial period was a combination of four easily administered cognitive measures (Fleisher et al., 2007). The results of these studies not only may help in diagnosing aMCI and AD, but also will be important in evaluating the efficacy of interventions to modify the progression of the disease.
  
  
• Investigators at the Washington University School of Medicine assessed the ability of biomarkers found in CSF to identify people who were likely to get AD (as defined by clinical criteria or the presence of beta-amyloid as shown with PiB on PET scans) within a group of nondemented older people (Fagan et al., 2007). Previous work has shown that levels of beta-amyloid in CSF typically decrease in AD, but that levels of tau in CSF increase. This study had three main findings. First, people with very mild symptoms of AD showed the same CSF biomarker profile as those in more advanced stages of the disease, suggesting that it may be possible to diagnose AD accurately at an early stage. Second, combining CSF amyloid measures with amyloid imaging in the PET scans revealed that low CSF amyloid levels can predict whether individuals have amyloid deposits in the brain, regardless of the presence of dementia. Information about CSF amyloid levels may therefore be a useful preclinical biomarker of AD. Third, the investigators found the same relative ratio of beta-amyloid and tau as earlier studies have done, suggesting that this ratio may have promise as a biomarker to predict future dementia in cognitively normal older adults.
  
  
• In recent years, scientists have become increasingly interested in the role of inflammation in AD. A research team at Beth Israel Deaconess Medical Center, Harvard Medical School, and Boston University conducted a study, supported by NIA, NHLBI, and NINDS, to assess whether the presence of markers of inflammation was linked to increased risk of AD (Tan et al., 2007). From 1990 to 1994, the researchers measured several inflammatory markers, including CRP, IL-6, IL-1, TNF-α, and IL-1-RA, in 691 original participants in the Framingham Study. The participants were then followed for 7 years to see whether they developed AD. Participants who produced the most of two markers, IL-1 or TNF-α, showed a greater risk of developing AD than those who produced the least. The researchers concluded that high levels of some inflammatory substances may be an early risk marker of AD, and that inflammation may play a role in AD development.
  
  
• Although people with aMCI are at high risk of developing AD, not everyone with aMCI goes on to develop AD. Researchers want to develop diagnostic markers that can predict whether someone with aMCI will eventually progress to AD. Two studies, by researchers at the University of California Davis and at Columbia University, used MRIs to monitor the extent of atrophy (shrinkage) in critical brain regions (DeCarli et al., 2007; Devanand et al., 2007). Both studies showed that atrophy of structures in the brain’s medial temporal lobe, including the hippocampus and entorhinal cortex (two structures heavily damaged by AD), could predict development of AD and the rate of progression from aMCI to AD. These results suggest that combining MRI tests with standard clinical tests during an evaluation of aMCI could help to identify which people with this condition are more likely to develop AD.
  
  To advance this area of diagnosis research, NIA and other Federal and private-sector organizations launched the AD Neuroimaging Initiative (ADNI) in 2004. ADNI is following about 200 cognitively healthy individuals and 400 people with aMCI for 3 years, and 200 people with early AD for 2 years. Early results from ADNI suggest that the data generated will help in evaluating disease progression and may reduce the time and expense of clinical trials by improving methods and developing uniform standards for imaging and biomarker analysis. ADNI also has created a publicly accessible database containing thousands of MRI and PET scan brain images as well as clinical data that is available to qualified researchers worldwide. More than 300 researchers already have accessed ADNI data and images, and ADNI has inspired similar efforts in Europe, Japan, and Australia.

In another relatively new area of AD diagnosis research, investigators are examining other types of physical changes that may hint at AD, opening the door to other potential tools to help clinicians diagnose AD early and accurately.

• Researchers have studied changes in visual abilities as a possible early indicator of aMCI or AD. Scientists at the Boston University School of Medicine found that, in some people with AD, tangles and plaques develop early in the disease process in the back of the cortex, a brain region deeply involved in visual processing (McKee et al., 2006). A second group of scientists, at the University of Rochester Medical Center, used several highly sensitive tests to examine how old age and AD affect various visual abilities, including “optic flow”—the way in which the surrounding environment appears to flow past as a person moves through space (Mapstone et al., 2006). The investigators found that in visual ability tests, healthy older people did better with optic flow than with other abilities, while those with AD had trouble with optic flow as well as other visual abilities. These findings may help create objective diagnostic tests for AD.
• Investigators at the Rush Alzheimer’s Disease Center in Chicago assessed whether impaired odor identification is related to increased risk of aMCI (Wilson et al., 2007). Consistent with previous studies, they found that, compared with people whose ability to identify odors was intact, those with impaired odor identification had a lower cognitive level and more rapid decline in certain cognitive abilities. More importantly, the researchers found that a person’s score on the odor identification test was able to predict the development of aMCI.
• Another study, conducted at the Rush University Medical Center, found that a higher level of frailty at the beginning of the study and a more rapid increase in frailty were both associated with an increased risk of developing AD (Buchman et al., 2007).

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