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New developments in neuroimaging and effective diagnostic tools can help obtain early diagnosis of and timely treatment for Alzheimer's disease.
Accurate and early diagnosis of Alzheimer's disease (AD) is vital to ensure patients receive the proper treatment, research is targeted correctly, and prevention and cures are found. However, it can be difficult to distinguish between AD and other forms of dementia, or even from other reversible disorders. The Alzheimer's Association has compiled an outline of the 10 most common symptoms associated with AD (Table 1) to help alert patients, caregivers and clinicians so that they can take action at the earliest signs of the disease. The earlier AD is diagnosed, the more treatable it is. The following is a review of some current tools used for diagnosis, and an update on research into promising new techniques for AD assessment.
Standard Assessment Tools
The standard tools for assessing AD include neuropsychological or cognitive evaluation, physical exam, neurological exam, laboratory testing, neuroimaging, behavioral assessment, and patient history. Many of these tests have been used for several years, and the question has been raised as to which are most effective.
Standard guidelines such as the DSM-III-R and those from the National Institute of Neurologic, Communicative Disorders and Stroke-AD and Related Disorders Association (NINCDS-ADRDA) have proven to be reliable resources for clinicians.
A recent meta-analysis of the diagnostic accuracy of these tests compared to neuropathologic confirmation from several studies revealed that both guidelines achieved an average of 81% sensitivity for a diagnosis of "probable" AD (Knopman et al., 2001). A diagnosis of "possible" AD achieved a very high sensitivity of 93%. Specificity for both diagnoses was lower, at 70% and 48%, respectively.
With respect to neuroimaging, magnetic resonance imaging, computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET) have all been used to assist in the diagnosis of AD. In a study cited by Knopman and colleagues (2001), when compared to neuropathologic confirmation, CT scans were 95% sensitive and 40% specific for diagnosing AD based on the width of the medial temporal lobe in 86 autopsied cases. The researchers also assessed the value of SPECT in two large studies of autopsy-confirmed diagnoses of AD. The SPECT results revealed sensitivities ranging from 86% to 95%, and specificities ranging from 42% to 73% when comparing patients with AD and non-AD dementia. In a smaller study, PET scans were reported to have a sensitivity of 93% and a specificity of 63%. Knopman and colleagues cautioned that imaging should be used in conjunction with other tests to increase the likelihood of an accurate diagnosis. Only noncontrast CT or MRI scans were recommended for use in routine initial evaluation of dementia patients. Neither SPECT nor PET imaging have proven to be superior to clinical criteria for AD.
Cognitive assessment is essential to the diagnosis and treatment of AD. There are several neuropsychological tests to assess the patient's cognition as well as their overall clinical condition. It is also important to measure their function in activities of daily living. Finally, caregiver-based interviews or questionnaires are useful for assessing behavioral disorders. A list of these assessment scales can be found in Table 2.
Genetic (e.g., apoliproprotein E genotyping) and cerebrospinal fluid markers have been used when assessing patients for AD. However, Knopman and colleagues do not recommend using these or other genetic markers to diagnose AD, primarily because clinical criteria are more sensitive. Comorbidities, such as depression, vitamin B12 deficiencies and hypothyroidism, should be evaluated.
One of the greatest challenges of assessing AD is whether the patient's symptoms reflect true AD, some other dementia or a different disorder altogether. The tools previously mentioned can assist in differential diagnosis, but it is important for clinicians to be aware of the subtle differences and characteristics that distinguish AD. The Alzheimer's Association provides a "Differential Diagnosis in AD Algorithm" outlining step-by-step procedures for diagnosing AD. It is available at <www.alz.org/PhysCare/Diagnose/procedure.htm>.
A majority of dementias such as vascular dementia (VaD), frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) are a result of vascular and degenerative brain diseases (Waldemar et al., 2000). In addition, inflammatory diseases, intra-cranial tumors and normal pressurehydrocephalus are rare symptomatic causes of dementia. According to the Alzheimer's Association, disorders that are associated with "reversible" dementia include depression, medication-induced dementia, hypothyroidism, B12 deficiency and systemic infections.
Lack of personal concern, disinhibition, indifference, compulsion and repetitive stereotyped behaviors demonstrate particular behaviors of FTD but are not typically seen in AD (Waldemar et al., 2000). Waldemar and colleagues also noted that early symptoms of DLB can include delusions and hallucinations. According to the Alzheimer's Association, VaD differs from AD in that the cognitive changes are typically associated with an onset within three months following a stroke, abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficit. Depression in elderly patients can manifest itself as confusion, memory disturbance and impaired attention, all of which are typically not seen in younger depressed patients. Alzheimer's disease may also coexist with depression, with each disorder exacerbating the other.
As mentioned earlier, patients with suspected dementia would benefit from structural neuroimaging studies such as MRI or CT in order to rule out brain diseases that can cause dementia. In the early stages of AD, changes in medial temporal lobe volume can be seen on MRI scans and, at times, on CT scans. In addition, MRI scans may show abnormalities of white matter or basal ganglia, which can affect diagnosis and/or prognosis of AD (Waldemar et al., 2000). Functional brain imaging such as SPECT and PET may be helpful when a clinical diagnosis of AD is questionable, but should not be used in place of a competent and confident clinical diagnosis (Knopman et al., 2001).
Although some studies find PET imaging useful for providing a differential diagnosis of dementia (e.g., Coleman, 2001; Silverman et al., 2001), researchers are still trying to find ways of improving imaging for use in AD. The latest research in PET imaging found that a new agent can help clinicians detect the actual plaques that cause AD. Prior to these findings, researchers could only detect plaques at autopsy. Jorge R. Barrio, Ph.D., professor of molecular and medical pharmacology at University of California, Los Angeles, and his colleagues came across this discovery during an attempt to locate proteins in the brain. They developed a molecule called 2-(1-(6-[(2-[18F]fluoro-ethyl)(methyl)amino]-2-naphthyl) ethylidene)malononitrile ([18F]FDDNP), which binds to the neurofibrillary tangles (NFTs) and ß-amyloid plaques (APs) in the brains of living patients with AD (Shoghi-Jadid et al., 2002). The researchers studied nine patients with AD and seven healthy controls. All subjects received neurologic, psychiatric and neuropsychological evaluations. They then were injected with [18F]FDDNP and subsequently scanned with fluorodeoxyglucose-PET (FDG-PET). The researchers' findings revealed that brain areas with low glucose metabolism, as a consequence of damage from NFTs and APs, were matched with high retention and localization of [18F]FDDNP. This correlated with lower scores on memory performance. In addition, the death of one patient allowed the researchers to compare the PET scan with brain tissue. They found that the patient had damage to the areas suggested by the PET scan.
The researchers hope that PET imaging with [18F]FDDNP will be used to detect neuronal damage before symptoms appear. "[Alzheimer's disease] remains silent for many years. By the time memory deficits appear, the disease is already advanced," Barrio told Psychiatric Times. As exciting as this discovery is, it also raises some issues. One is the question of who should be tested. If the idea is to catch the disease before symptoms appear, then anyone appearing normal should be tested. This method is not practical for obvious reasons. Second, once a patient is tested, the appearance or absence of plaques does not guarantee or dismiss a diagnosis. According to Barrio, healthy adults can have plaques in their brains without ever developing AD. Finally, if a patient is found to have a substantial number of plaques in their brain, what actions should be taken? "It's not a good idea to only provide early diagnosis and no hope," said Barrio. "The pharmaceutical industry is working very hard to develop drugs that will prevent formation of plaques." In addition, Barrio and his team are working on 25 to 30 additional compounds to optimize the resolution in the scans.
With the intent of determining predictors of AD, findings from a study published in Archives of Neurology may also provide tools for diagnosing AD (Marquis et al., 2002). Researchers at University of Alberta in Canada studied 108 adults 65 years or older who were healthy at the start of the study. After an average of 3.7 years, 48 of these subjects progressed to questionable dementia. The researchers found that those with dementia entered the study with three traits in common: slower gait, lower scores on memory tests and minor shrinkage in the hippocampus as measured by MRI. Each of these changes was very subtle, but physicians may want to take these traits into consideration when evaluating older patients.
With the multitude of tools available for diagnosing AD, physicians need to be selective in choosing the methods that are right for them and their patients. Time, cost, accuracy and convenience are factors physicians and researchers need to take into consideration. Fortunately, as more tools become available, physicians will have a better chance of accurately diagnosing AD. Most important, physicians must take care to diagnose their patients early in the disease and treatment process.
Coleman RE (2001), Positron emission tomography in the evaluation of dementia. Presented at the 48th Annual Meeting of the Society of Nuclear Medicine. Toronto; June 23.
Knopman DS, DeKosky ST, Cummings JL et al. (2001), Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56(9):1143-1153 [see comments].
Marquis S, Moore MM, Howieson DB et al. (2002), Independent predictors of cognitive decline in healthy elderly persons. Arch Neurol 59(4):601-606.
Shoghi-Jadid K, Small GW, Agdeppa ED et al. (2002), Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 10(1):24-35.
Silverman DH, Small GW, Chang CY et al. (2001), Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 286(17):2120-2127 [see comments].
Waldemar G, Dubois B, Emre M et al. (2000), Diagnosis and management of Alzheimer's disease and other disorders associated with dementia. The role of neurologists in Europe. European Federation of Neurological Societies. Eur J Neurol 7(2):133-144 [see comment].