September 15, 2004, marked an important milestone for all those involved in the diagnosis, treatment, and care of patients with Alzheimer’s disease (AD), which in the United States currently afflicts more than 4 million people and may cost our health care system more than $100 billion annually. 1-4 On this date, the Centers for Medicare and Medicaid Services (CMS) approved the use of [ 18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in diagnosing the cause of dementia in patients with at least 6 months of documented cognitive decline. Historically, with the dearth of definitive diagnostic tests, AD often has been diagnosed only after other causes of dementia have been excluded. Diagnosis is important to initiate early treatment, which may delay disease progression and prepare family members and other caregivers to care for the patient. Moreover, the pathophysiology of AD is still shrouded in mystery, preventing the development of adequate treatments. With its ability to image brain physiology, PET could play a valuable role in diagnosing, managing, and further elucidating the causes and potential treatment of the disease.

ALZHEIMER’S DISEASE

AD is a devastating disease with dementia ultimately progressing to a point where patients can no longer perform daily functions. Although it is the most common cause of dementia in older individuals, AD is not the only cause. 5 Fronto-temporal dementia (FTD), dementia with Lewy bodies (DLB), Creutzfeldt-Jakob disease (CJD), and cerebrovascular disease resulting in vascular dementia (VAD) are possibilities as well. 6 Moreover, other problems such as depression, medication toxicity, or metabolic disorders like hypothyroidism can cause symptoms mimicking dementia.

While AD has characteristic histologic findings on brain autopsy (neuronal plaques, neurofibrillary tangles, and neuronal loss), there have been no clear-cut clinical findings or laboratory tests to definitively establish the diagnosis pre-mortem. Laboratory tests can exclude metabolic, infectious, and drug-induced causes, and MRI and CT can rule out certain anatomic causes such as neoplasms and hematomas. The degree of cognitive impairment is often not revealing, as studies have shown that patients with typical AD histologic lesions may not have any cognitive impairment. In addition, patients may have a combination of AD and other potential causes of dementia, most often cerebrovascular disease. AD diagnostic criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer’s Disease and Related Disorders Association (NINCDS—ADRDA) have been found to be 0.65 sensitive and 0.75 specific. 7

Differentiating between AD and other causes of dementia is important since the natural history and management differ. For example, deficits of judgment and conduct in FTD appear earlier and seem to be less responsive to AD treatments. 6 While there is no cure for AD, certain therapies may have some effect in slowing progression or alleviating symptoms of the disease and therefore are regularly used. Cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) are approved for the treatment of mild-to-moderate AD, and memantine, an N-methyl-D-aspartate antagonist, is approved for moderate-to-severe disease. There is some evidence that antioxidants, specifically alpha-tocopherol (vitamin E), may delay disease progression. As a result, many practitioners have added high-dose vitamin E supplements (2,000 IU daily) to their standard treatment regimen for AD. Herbal medications, such as ginkgo biloba and huperzine A, have shown some promise. Ongoing studies are looking at antiamyloid therapies and neuroprotective agents. 7,8

Nonpharmacological interventions are also a significant part of AD management. Exercise, sensory stimulation, and relaxation techniques may have beneficial effects. Knowing that a patient has AD can help prepare caregivers and family, who must be ready to provide extensive assistance, help administer therapies, serve as a liaison for health care providers, and make important social and economic decisions. 9

PET AND AD

Figure 1. Normal axial positron [18F]-fluorodeoxyglucose (FDG) emission tomography (PET) images of the brain. (Click the image for a larger version.)

PET has been widely used to study many aspects of brain physiology and various central nervous system disorders. There are a number of radiopharmaceuticals labeled with positron-emitting isotopes, including carbon-11 ([ 11 C]), fluorine-18 ([ 18 F]), and nitrogen-13 ([ 13 N]), that can be used to measure cerebral blood flow (CBF), cerebral metabolism, and neurotransmitter systems. FDG, the most commonly used radiopharmaceutical, is relatively easy to produce and use and can provide high-resolution images of cerebral glucose metabolism.

Initial 18 F-FDG PET studies showed that AD patients have a 20% to 30% decrease in whole-brain glucose metabolism (CMRGlc) values compared with healthy age-matched controls, particularly in the bilateral parietal and temporal lobes. 10-13 Figure 1 shows a normal PET scan. By contrast, FTD patients generally tend to show bifrontal and bitemporal glucose hypometabolism with sparing of the parietal lobes 14 (Figure 2). Vascular dementia tends to result in asymmetric and focal areas of hypometabolism. In Pick’s disease, the most common PET finding is bilateral frontal and anterior temporal lobe hypometabolism, the same place where Pick’s bodies are seen on histopathologic examination. 13,15

Figure 2. Sagittal FDG-PET images of patient with fronto-temporal dementia (FTD) demonstrating frontal hypometabolism (arrow). (Click the image for a larger version.)

While not pathognomic for AD (as it can be seen in Parkinson’s disease, bilateral parietal subdural hematomas, bilateral parietal stroke, and bilateral parietal radiation therapy ports), this bilateral parietal pattern is highly predictive of AD and may be particularly pronounced in patients with an age less than 65 years. 16-18 Moreover, the magnitude and extent of hypometabolism correlate with the severity of the dementia symptoms, with only minor parietal lobe decreases in early mild AD (Figure 3); significant left midfrontal, bilateral parietal, and superior temporal region decreases in moderate AD; and even more severe hypometabolism in these regions with sparing of only sensorimotor, visual, and subcortical areas in severe AD (Figure 4). The rates of decrease over time seem to be greater for AD patients than age-matched control subjects. 19-21

Figure 3. Axial FDG-PET images of patient with early Alzheimer’s disease (AD). Note (arrow) the minor parietal hypometabolism.

The ability of PET to measure changes in neurotransmitter systems may be important in the future. For example, loss of cortical acetylcholine occurs in AD and suggests the pathophysiological reason why cholinesterase inhibitors are used as therapy. In one study of AD patients, significant decreases in acetylcholinesterase activity were seen in the neocortex, hippocampus, and amygdala, suggesting a loss of cholinergic innervation in the basal forebrain. The temporal and parietal cortices were the most affected, although reductions were relatively uniform in the cerebral neocortex. 22

New radiopharmaceuticals for imaging the amyloid plaques in AD patients have been developed. For example, the Pittsburgh Compound B was found to be selective to the amyloid plaque and capable of differentiating AD patients from controls. 23 Future studies will be required in order to determine how early in the course of the disease such compounds might be useful and how well they can differentiate other causes of dementia.

Figure 4. Axial FDG-PET images of patient with late stage AD. There is severe parietal and temporal hypometabolism in these regions with sparing of only sensorimotor, visual, and subcortical areas.

PET also can play an important role in evaluating AD therapeutic interventions by comparing the effects of different therapies and placebo on cerebral metabolism and neurotransmitter activity. For example, such studies already have been done on donepezil and rivastigmine. 24,25 PET studies have found that the therapeutic responses to these drugs may be related to their effects on acetylcholinesterase activity primarily in the frontal lobes. 25,26

AD PET PROTOCOLS

In terms of PET protocols, it is ideal if imaging can be performed on a dedicated brain PET scanner. 27 However, whole body scanners can still perform adequately for determining the overall metabolic pattern and help in the diagnosis of AD. Most patients are asked not to eat after midnight, and blood glucose is checked prior to injection of FDG. High serum glucose may affect the sensitivity or specificity of the PET scan findings. It is also important to standardize the environment during injection since any sensory or motor function might affect cerebral glucose metabolism. Patients should be in low stimuli environments with dim lighting and low ambient room noise. Patients should be told not to talk or partake in any activity for approximately 30 minutes after the injection. It is also important to assess for medication use, especially those that might affect cerebral glucose metabolism such as anxiolytics or sedatives. Scanning usually begins approximately 30 minutes after injection and lasts for approximately 30 minutes.

Images can be reconstructed by a variety of means that should account for dose, body size, patient motion, the capabilities of the scanner, and attenuation. Once available for interpretation, there are a number of ways of evaluating the scans. Scans can be interpreted in a purely qualitative manner describing areas of abnormal metabolism and considering the overall pattern. Alternatively, scans can be read utilizing a semiquantitative approach or fully quantitative approach.

As one example, our research group developed the Metabolic Imaging Severity Rating Scale (MISRS), a semiquantitative subjective scoring system to assess AD severity, which may be useful for routine clinical use and research studies. To calculate the MISRS, the metabolic activity of each anatomic structure on the PET scan is assigned a score using either a more quantitative method with region of interest templates to calculate the mean number of counts in each structure or a more qualitative visual inspection method by assigning a score of 0 to 4 for each structure (4 = normal activity; 3 = mildly decreased activity; 2 = moderately decreased, 1 = severely decreased; and 0 = no activity). The MISRS is comprised of two scores: Score I is the sum of the visual cortex, sensorimotor cortex, thalami, cerebellum, and the basal ganglia (areas not typically associated with cognitive impairment), and Score II is the sum of the frontal, temporal, and parietal cortices (areas typically associated with cognitive impairment). The MISRS is the percentage difference between the activity in the areas typically affected in cognitively impaired patients and the activity in those areas not typically affected and is calculated using the following formula: 200 (score I – score II)/(score I + score II). A score of 50 is normal (ie, all brain regions have a score of 4). The higher the score, the more affected are the frontal, temporal, and parietal cortices. Our group found close correlations between the qualitative and quantitative MISRS as well as both MISRS scores with the patient’s level of cognitive impairment as measured by the Mini-Mental State Examination (MMSE) and the Dementia Severity Rating Score (DSRS). 28 Future studies will determine if normal databases might be available for comparing individual subjects and determining where abnormalities exist so that accurate diagnoses might be made.

REIMBURSEMENT

On September 15, 2004, CMS announced that there was adequate evidence to support the use of FDG-PET in patients with documented cognitive decline of at least 6 months and a recently established diagnosis of dementia who meet diagnostic criteria for both Alzheimer’s disease and fronto-temporal dementia. 29 They stipulated that the patient must have been evaluated by a physician experienced in the assessment of dementia and underwent a comprehensive clinical evaluation, as defined by the American Academy of Neurology (including a detailed medical history and physical examination, mental status examination with cognitive scales or neuropsychological testing, laboratory tests, and anatomic imaging such as MRI or CT), which was not able to establish a cause of the dementia.

CMS also specified that the FDG-PET scan must be performed in an accredited facility and interpreted by a nuclear medicine physician, radiologist, neurologist, or psychiatrist experienced in interpreting such scans and a brain single photon emission computed tomography (SPECT) or FDG-PET scan has not already been obtained for the same indication. In case the results of a SPECT or FDG-PET scan are equivocal, 1 year must pass before another FDG-PET may be obtained and covered.

Moreover, the referring and billing providers must document the date of onset of symptoms, a MMSE or similar test score, reports from any neuropsychological testing performed, a diagnosis of the clinical syndrome (eg, mild cognitive impairment; dementia), presumptive causes (possible, probable, uncertain AD), results of structural imaging (MRI or CT), relevant laboratory tests (B12, thyroid hormone), and the number and names of prescribed medications. The billing provider also may be required to furnish a copy of the FDG-PET scan result to CMS and its contractors for Medicare quality assessment and improvement activities.

In the same September 15, 2004, coverage memo, CMS indicated that it did not approve the general clinical use of FDG-PET in diagnosing patients with mild cognitive impairment or early dementia, unless it is part of a formal clinical trial that compares patients who do and do not receive FDG-PET scans and aims to monitor, evaluate, and improve clinical outcomes. In such a trial, a written protocol must be on file and reviewed and approved by the hospital’s or research center’s Institutional Review Board and two or more qualified individuals not part of the research team.

CMS assigned a Healthcare Common Procedure Coding System (HCPCS) code of G0336 for PET imaging of the brain for Alzheimer’s. Details on coverage and billing requirements can be found in the Medicare Claims Processing Manual, Publication 100-04, Chapter 13, Section 60.

SUMMARY

The September 2004 CMS decision to cover the use of FDG-PET to help diagnose dementia adds an important modality to the arsenal of clinicians and researchers. Subsequent studies may better define the role of FDG-PET in evaluating mild cognitive impairment and potentially lead CMS to expand its coverage in the future. Earlier diagnosis and a better understanding of AD pathophysiology may have significant clinical, social, and economic benefits. As PET technology and radiopharmaceuticals improve, the use of PET in the clinical and research arenas to evaluate dementia will likely grow.

Bruce Y. Lee, MD, MBA , is assistant professor, Division of General Internal Medicine, University of Pittsburgh.

Andrew B. Newberg, MD, is assistant professor, Department of Radiology and Psychiatry, University of Pennsylvania Health System, Philadelphia.

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