Michael D. Devous, Sr, PhD

In the United States, approximately two thirds of the cases of dementia now diagnosed are Alzheimer’s disease. There is tremendous overlap, however, between Alzheimer’s disease and vascular dementia. Additional overlap occurs between Alzheimer’s disease and the Lewy body and Parkinson types of dementia. Although separate diagnoses of these forms of dementia are obviously being made based on the signs and symptoms of living patients, even the pathology noted at autopsy shows considerable blurring of the lines separating these disease entities. Differential diagnosis for dementia, therefore, can be extraordinarily difficult.

The economic consequences of Alzheimer’s disease are also severe: it is the third most expensive disease in the United States, with a cost estimated at more than $100 billion per year (in addition to $33 billion per year in lost productivity and other employer costs). 1 Three fourths of Alzheimer’s patients are admitted to residential care within 5 years of diagnosis, contributing to the massive expense associated with the disease.

Given the severity, prevalence, and cost of Alzheimer’s disease, considerable potential exists to improve diagnosis and treatment levels across disease stages (Figure 1). Most mild cases of Alzheimer’s disease are not even diagnosed; of those cases that are diagnosed, only about two thirds are treated. In moderate cases, the same pattern emerges: most cases are not diagnosed (despite the patients’ moderate cognitive symptoms), and only two thirds to three fourths of those diagnosed with Alzheimer’s disease of moderate severity are treated. In severe cases, it is much easier to make a diagnosis of Alzheimer’s disease, so almost all cases are diagnosed, but less than half of those diagnosed are treated. Why is this the case? Why do some clinicians believe that mild Alzheimer’s disease fails to benefit from treatment? Why would any patient with a severe case of Alzheimer’s disease be left untreated?

THE IMPACT OF INTERVENTION

Figure 1. (Top) Potential increases in treatment and diagnosis across Alzheimer’s disease stages; AChE=acetylcholinesterase. (Click the image for a larger version.)

Perhaps there is a misunderstanding of current therapeutic options that leads some physicians to believe that it is pointless to treat patients with severe Alzheimer’s disease. Clinical experience appears to indicate that this is not the case. Likewise, it is valuable to make an early diagnosis based on the behavioral symptoms of mild Alzheimer’s disease and related dementias. The potential impact of intervention on delaying the onset of Alzheimer’s disease (Figure 2) is, in fact, enormous. There are about 4 million people with Alzheimer’s disease in the United States today, and this figure is expected to climb to more than 9 million affected individuals by 2047. If the symptoms of Alzheimer’s disease could be delayed by only 5 years, the overall incidence of the disease would be cut in half. A 10-year postponement of Alzheimer’s symptoms would cause the virtual disappearance of the disease, as the patient’s life would almost certainly be taken by some other more fatal disease, such as heart disease or cancer. Therefore, therapy using medications that prevent the occurrence or emergence of symptoms of Alzheimer’s disease can be of tremendous benefit, not only to patients, but also to society as a whole.

Figure 2. (Bottom) Intervening to delay the onset of Alzheimer’s disease by 5 years could reduce prevalence by half; AD=Alzheimer’s disease. Both figures are taken from a presentation entitled The Treatment of Alzheimer’s Disease and Disease Progression Modification by Steven G. Potkin, MD, professor, Department of Psychiatry and Human Behavior; director, Clinical Psychiatric Research; Robert R. Sprague Director of UCI Brain Imaging Center, University of California, Irvine. (Click the image for a larger version.)

In Alzheimer’s disease, neuronal degeneration clearly precedes the emergence of clinical symptoms, and the disease is characterized by a presymptomatic phase that is likely to last for years. The challenge for medicine, then, is to identify individuals during the preclinical period because this will allow symptom-delaying therapy to begin during that phase. This preclinical identification of patients who will develop Alzheimer’s disease can be accomplished through the improvement of mechanisms for early detection and through the development of tools that make diagnosis possible during an earlier part of the temporal course of the disease.

In Alzheimer’s disease, the expanded ability to perform preclinical diagnosis could make it possible to

  • identify groups at risk for both disease onset and progression,
  • accelerate and enhance the accuracy of diagnosis in the early clinical phase (to ensure appropriate treatment),
  • speed development of drugs to modify disease progression, and
  • enable therapies directed at individuals in the preclinical phase to prevent or slow the onset of clinical manifestations.

The strategies employed could include both therapies specific to the pathobiology of Alzheimer’s disease (such as the use of antiamyloid medications) and interventions that address nonspecific disease mechanisms such as inflammation or oxidative stress.

DIAGNOSTIC METHODS

Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are useful in caring for patients with dementia both for early detection of Alzheimer’s disease and for the differential diagnosis of various forms of dementia. In one reported series 3 involving 284 dementia patients and 138 autopsy-confirmed diagnoses, PET scanning had a sensitivity of 93% and a specificity of 76%. A negative PET scan indicated a chance of cognitive decline of less than 20% over the ensuing 3 years. This study shows that PET can be useful in the evaluation of dementia (particularly early dementia) when there is a question of whether the patient’s mild cognitive impairment is due to normal aging or is the harbinger of Alzheimer’s disease.

A study 4 of SPECT in the evaluation of 108 dementia patients found that SPECT examination had a sensitivity of 89.5%, a specificity of 81.5%, a positive predictive value of 93.2%, and a negative predictive value of 73.3%. A meta-analysis 5 of SPECT’s usefulness in evaluating dementia reviewed 46 reports of studies involving 965 patients and 527 controls. This work found a sensitivity of 89% and a specificity of 97% for SPECT in differentiating healthy subjects from those with Alzheimer’s disease. In addition, SPECT permitted differentiation of subjects with Alzheimer’s disease from those with other dementias with a sensitivity of 75% and a specificity of 84%.

BEYOND DIAGNOSIS

Important as PET and SPECT imaging are likely to be for the diagnosis of Alzheimer’s disease, they can also serve other purposes in the care of patients with dementia. For example, receptor imaging (PET) can be used to distinguish between Alzheimer’s disease and dementia with Lewy bodies; regional cerebral blood flow (SPECT) imaging can be used to distinguish between Alzheimer’s disease and frontotemporal dementia; individuals can be compared to normative databases; a patient’s response to therapeutic intervention can be monitored; a single subject’s risk status can be examined; and most recently, imaging agents have been developed such that amyloid deposits can be detected. When these applications for PET and SPECT reach broad clinical use, the benefit to patients with Alzheimer’s disease and other dementias could be immense.

Michael D. Devous, Sr, PhD, is professor of radiology and director of the neuroimaging core for the Alzheimer’s Disease Center, University of Texas Southwestern Medical Center, Dallas. This article has been excerpted from Functional Brain Imaging in the Dementias: Toward a Cure for Alzheimer’s Disease, which he presented at the 52nd annual meeting of the Society of Nuclear Medicine on June 19, 2005, in Toronto.

References:

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