Daniel H.S. Silverman, MD, PhD and Gary W. Small, MD, Departments of Molecular and Medical Pharmacology, and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles School of Medicine, Los Angeles, CA

Volume 1 * Issue 3 February 2003

Category 1 CME

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PET in the Evaluation of Alzheimer's Disease and Related Dementias

Alzheimer's disease (AD) is the leading cause of dementia. Four million people in the United States currently suffer from AD. It is estimated that it will affect as many as 14 million people nationwide as the baby boomer generation ages, while the economic toll exerted on society already approaches $100 billion. ^1-4 Fortunately, significant advances in the treatment of AD have emerged over the past decade. This in turn has added substantial impetus to the need to recognize and accurately diagnose AD, and to specifically distinguish it from the many other potential causes of cognitive impairment. This article focuses on the contribution that measuring brain metabolism with PET can make to the process of evaluating patients with symptoms of dementia, and describes how the appropriate use of PET adds to conventional imaging and clinical evaluation.

CONVENTIONAL NEUROIMAGING IN DEMENTIA ASSESSMENT

When neuroimaging is obtained in the evaluation of dementia, patients are usually referred for a structural imaging examination--i.e., MRI or CT of the brain. Conventional MRI or CT of patients with symptoms of dementia may be useful for identifying unsuspected clinically significant lesions, present in approximately 5% of patients. ⁵ However, in patients with AD, which is much more common, such scans are typically read as normal, or as demonstrating the nonspecific finding of cortical atrophy or, worst still, as revealing ischemic changes that are (mis)interpreted as pointing to cerebrovascular disease as the primary or sole process responsible for the patient's cognitive decline. Such misinterpretations may lead, in turn, to failure to institute appropriate pharmacotherapy (e.g., donepezil, rivastigmine, or galantamine, all of which are FDA-approved only for the indication of "mild to moderate dementia of the Alzheimer's type.") It is unfortunately not rare for that type of misinterpretation to occur, even among expert clinicians. Victoroff et al reported the results of their multicenter study, involving seven university-affiliated Alzheimer's Disease Diagnostic and Treatment Centers. They studied patients diagnosed after clinical and structural neuroimaging evaluations as having "vascular dementia," in whom other dementia diagnoses were specifically thought to be absent. They found that <30% of those patients actually had isolated cerebrovascular disease, and the majority (55%) had AD upon pathological diagnosis. ⁶

Despite substantial variability in qualitative interpretation of atrophy on CT and MRI studies, even among expert readers, ^7-9 some studies have reported differences in qualitative assessments of mesiotemporal atrophy between groups of patients with and without AD. One of the largest studies to obtain such data examined T1-weighted coronal MRI slices of 222 subjects, composed of 77 patients thought to have AD, 105 patients having neuropsychiatric complaints but thought to not have AD, and 40 healthy control subjects. ¹⁰ The anterior hippocampus had the highest sensitivity for identifying the AD patients (83%), with a similar specificity (85%) and overall accuracy. In the current context, however, several limitations of this generally well-designed study--which are in fact shared by most published studies of this type--must be noted. First, the patient groups were not matched for severity of cognitive symptoms. Mean Cambridge Cognitive Examination (CAMCOG) scores in healthy subjects, non-AD and AD patients were 96, 81, and 58, respectively; Mini-Mental State Examination (MMSE) scores were 28.5, 25, and 17. By either measure, the average cognitive status of the non-AD dementia controls was actually closer to that of the normal subjects than to that of the AD patients. It is thus unclear whether the mesiotemporal atrophy identified by the authors bore any relationship to the specific diagnosis, as opposed to simply the severity of disease. Estimates of specificity based on those data will likely be overestimated. Second, dementia symptoms were far from being categorizable as early: AD patients were on average >70 years old and had mean duration of reported cognitive decline of 46 months, with their mean CAMCOG and MMSE scores of 58 and 17 further attesting to the moderately advanced status of their disease. Finally, only 4 participants (<2%) underwent postmortem confirmation of diagnosis; hence the true sensitivity and specificity for MRI diagnosis of AD in the population of the study remains unknown.

Recent innovations in the MR field, involving functional and spectroscopic applications, as well as measurement approaches (volumetric, planimetric, and linear) applied to CT and MR, have raised anew the question of potential utility of structural imaging in the diagnosis of Alzheimer's disease. For example, in an effort to overcome problems of subjectivity in qualitative interpretations of atrophy, a number of investigations have tried to enhance the diagnostic utility of CT or MRI in dementia by quantifying the sizes of specific regions of the brain (especially mesiotemporal structures), or of the whole brain. ^11-13 Results have varied, depending in part on the specific measurement approaches taken, and many investigations suffer from limitations similar to those described for the qualitative mesiotemporal atrophy study detailed above: i.e., lack of matched control groups adequately representing patients with non-AD dementias, as would comprise a realistic patient mix, and/or comparisons to diagnoses established clinically, without pathologic confirmation. In general, however, investigators attempting to characterize early stages of AD using quantitative MRI assessments of hippocampal atrophy have found considerable overlap between AD patients and control subjects, and clinical utility of such measurements in the diagnosis of AD (especially at an early stage) remains to be established.

Another approach for utilizing MRI in the workup of dementia has centered on recent technologic developments that enable the use of that instrumentation to yield biochemical or physiologic, rather than anatomic, information. Magnetic resonance spectroscopy imaging (MRSI) has been used to measure levels of the neuronal metabolite N-acetyl aspartate (NAA) in patients with AD in order to assess neuronal loss. Schuff et al ¹⁴ employed this methodology to examine hippocampal NAA in possible or probable AD patients with a "mild or moderate level of dementia severity," and age-matched healthy control subjects. No subjects with dementia of other etiologies were included, however. In 25% of AD patients, MRSI data was unobtainable or unusable, due to either patients' intolerance of the confining MRI scanning environment, or to poor spectral quality. On an "intention-to-diagnose" basis, a stepwise linear discriminant analysis would yield optimal separation of AD from healthy subjects with a 67% detection rate for AD, and would increase to 75% when MRSI information was coupled with volumetric measures of hippocampal atrophy to identify AD patients.

Other modes for acquiring MRI data are undergoing evaluation. Hanyu et al ¹⁵ recently used a diffusion-weighted (DW) imaging technique to detect white-matter changes in patients with AD. A significant difference was found between average anisotropic ratios in the white matter of AD and control groups. When viewed individually, however, ratios for subjects from each group overlapped markedly. Several other investigators have begun to examine differences between normal subjects and those who are at increased risk for developing dementia, with respect to their regional blood flow activation patterns, as assessed by blood oxygenation-level dependent (BOLD) or similar functional MRI methods. ^16,17 It is too early to know what role, if any, procedures such as MRSI, DW, and BOLD MRI may come to play in the clinical evaluation of early stages of dementia.

IMPORTANCE OF EARLY DIAGNOSIS AND TREATMENT

Patients and caregivers often mistake early symptoms of AD for normal changes of aging , and physicians may fail to recognize the initial signs of dementia or misdiagnose them, perpetuating myths and fallacies about the disease, particularly, that the early signs of dementia are "just old-age" or "just senility."

Early and accurate diagnosis may prevent the use of costly medical resources and allow patients and their family members time to prepare for future medical, financial, and legal challenges. While no current therapy can reverse the progressive cognitive decline of AD, several pharmacologic agents and psychosocial techniques have been shown to provide relief for the depression, psychosis, and agitation often associated with dementia. Also, cholinesterase inhibitor drugs slow cognitive and functional decline and produce cognitive improvement in many patients. Yet, some primary care physicians, who are the port of entry for most patients with early-stage dementia, remain uninformed and thus unable to diagnose, treat, and manage these patients effectively. Community-wide prevalence surveys detect many undiagnosed cases. Research has shown that physicians often fail to apply a diagnosis of dementia correctly, making a positive diagnosis when the disease is not present or failing to recognize it when it is. ^18,19 In 1997, a consensus conference on dementia, sponsored by three major national professional organizations, concluded that, "Given the large number of older Americans likely to become cognitively impaired, primary care physicians require more effective strategies to recognize the disease's early signs and symptoms." ²⁰

Recent studies point to the importance of early detection and treatment with cholinesterase inhibitor drugs. Raskind and colleagues ²¹ used a randomized, placebo-controlled design to study the cholinesterase inhibitor galantamine in patients with mild to moderate AD. They found that the drug significantly improved cognitive function compared with placebo after 6 months of treatment. During the following 6-month open-label treatment period, the patients who were originally treated with placebo were given active drug, and at 1 year, better cognitive performance was observed in patients who began drug treatment from the beginning of the trial compared with those who had been placebo-delayed for 6 months. Delaying the initiation of therapy with either rivastigmine or donepezil has yielded similar detrimental effects. ^22,23

RECENT STUDIES ON THE ACCURACY OF PET IN DEMENTIA EVALUATION

Over the last two decades, clinicians and researchers have obtained substantial experience in using the three-dimensional imaging capabilities of positron emission tomography (PET) for the identification and differential diagnosis of dementia. ²⁴ Thousands of patients with clinically diagnosed and, in some cases, histopathologically confirmed, Alzheimer's Disease from many independent laboratories and clinics have been scanned using measures of glucose uptake, and in some cases blood flow or oxygen utilization, obtained through the use of PET with tracers appropriate to studying those biologic processes. Briefly, the principal findings that have emerged from that experience are: a consistent pattern of focally decreased cerebral metabolism and perfusion has been identified, which involves especially posterior cingulate and neocortical association cortex, but largely spares basal ganglia, thalamus, cerebellum, and cortex mediating primary sensory and motor functions (Figure 1).

Studies comparing neuropathologic examination with PET imaging are the most informative in assessing diagnostic value. In the largest such single-institution series, Hoffman and co-workers, ²⁵ studied 22 patients with various types of dementia (including 64% with Alzheimer's disease alone, and 9% with Alzheimer's plus additional neurologic disease, identified by pathologic diagnosis). Visual interpretation of scans, made by readers blinded to clinical information, yielded estimates of sensitivity and specificity for identifying the presence of Alzheimer's disease of 88% to 93% and 63% to 67%, respectively. Recently, a multicenter study was organized, to compare dementia diagnosis using FDG-PET with neuropathologic diagnosis. ²⁶ The investigators collected data from an international consortium of clinical facilities that had acquired both brain FDG-PET and histopathologic data for 138 patients undergoing evaluation for dementia. Images and pathologic data were classified independently as being positive or negative for 1) presence of a progressive neurodegenerative disease in general, and 2) AD, specifically. The PET results identified patients with AD, and patients with any neurodegenerative disease, with a sensitivity of 94% in both cases, specificities of 73% and 78%, and overall accuracies of 88% and 92%. ²⁶

How does this compare with the sensitivity and specificity of clinical evaluation? In the recent report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN), ⁵ the source of the most comprehensive and authoritative guidelines and standards for the clinical evaluation of dementia in the last several years, three "Class I" studies were identified in which the diagnostic value of their recommended (conventional) clinical assessment could be measured meaningfully. ^27-29 (Class I indicates "a well-designed prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, and enabling the assessment of appropriate tests of diagnostic accuracy.") If one accepts the recently affirmed recommendation of the AAN ⁵ that the NINCDS-ADRDA criteria for "probable AD (rather than the more inclusive "possible AD") should be routinely used," then clinical sensitivity ranges in the interval of 66% ± 17%, while the sensitivity using PET ranges in the interval of 91% ± 3%. The sensitivity of clinical evaluation can be increased to 90.5% ± 5.5% (comparable to that using PET) by expanding the diagnosis of AD to include patients who meet NINCDS-ADRDA criteria for "possible AD," but at the expense of specificity (55.5% ± 5.5% in the Class I studies). In contrast, at that level of sensitivity, the specificity using PET is 70% ± 3%. ^25,26 Only one of the Class I studies focused on evaluating dementia at a relatively early stage. ²⁷ To be included in that investigation, patients were required to have had onset of dementia symptoms within 1 year of entry. All of the 134 patients evaluated underwent a complete standardized diagnostic work-up, comprised of a comprehensive medical history and physical examination, neurological examination, neuropsychologic testing, laboratory tests, and structural neuroimaging, as well as an average of 3 additional years of clinical follow-up. Sensitivity of this assessment for AD was 83% to 85%, while specificity was 50% to 55%. It should be emphasized that this was not the diagnostic accuracy of initial clinical evaluation, but of an entire series of evaluations repeated over a period of years.

The AAN subcommittee reviewed nine additional studies that addressed the clinical diagnostic accuracy of AD, ⁵ but which they classified as having lower "quality of evidence" than those described above. Across all these studies, they found an average clinical specificity of 70% (as occurs with PET), while average sensitivity in that analysis was 81% (compared with the 91%± 3% reported for PET). In the two largest Class II studies that uniformly employed NINCDS-ADRDA diagnostic criteria, at a sensitivity of 90% ± 1% (achieved by including "possible AD" patients), specificity fell to 29% ± 8%. ^6,30

FINANCIAL CONSIDERATIONS AND THE CLINICAL ROLE OF PET

With a preponderance of evidence pointing to improved accuracy when PET is incorporated into the diagnostic algorithm for evaluation of early dementia, the focus then turns to the question of exactly when it should be obtained. Beyond the specific advantages of more accurate diagnosis, leading to more appropriate management, several other ramifications of having the added information provided by PET bear upon this issue. As alluded to earlier, if accurate positive diagnoses are achieved early in the disease process, patients and their families could be spared the repeated batteries of diagnostic tests performed over extended periods of time, they and their physicians less often experience the frustrations of ambiguous diagnostic conclusions, and the information would also enhance the ability of families to plan for issues pertinent to future patient care. ³¹ The ability to plan for future care may be particularly important in light of recent data indicating that the degree of hypometabolism identified by PET in certain affected brain regions predicts the rate of decline in standardized measures of memory that takes place in the years subsequent to PET examination. ³¹

These and other considerations support the notion that the best time to obtain PET is early in the course of the clinical work-up, as soon as it has been determined that it would be appropriate to include PET in the evaluation of cerebrocortical dysfunction. The guiding principle for that determination is simply as follows: a patient who presents with an adverse change in cognition or behavior, which has not been both fully explained and fully reversed following standard diagnostic and treatment approaches, should be considered a candidate for PET imaging.

How much will following such a recommendation cost us and, more to the point, how does that compare with the costs incurred when the additional information provided by PET is not available? The cost associated performing a dedicated brain PET amounts to less than the typical costs of 1 year of pharmacotherapy for unnecessary treatment of a patient misdiagnosed with AD, or 1 month of lost productivity and independence of a patient for whom we fail to provide timely diagnosis and treatment. In a recent examination of the extent to which the costs of scanning would be offset by the costs saved through improved diagnostic accuracy, employing the formalized tools of decision analysis, it was found that the added diagnostic accuracy obtained by incorporation of FDG-PET into the routine clinical evaluation of patients presenting with early symptoms of dementia could be achieved in an economically practical manner. ³² In fact, the attendant improvement in accuracy allowed PET scans to essentially pay for themselves for all reimbursed costs of brain PET lower than approximately $2700. (The amount that is currently reimbursed for brain PET is typically hundreds of dollars below that figure.) Moreover, recent developments in instrumentation strategies, commercial PET radiopharmaceutical distribution, and reimbursement policies, are rapidly making PET widespread. During the next few years, PET will likely become available virtually anywhere general nuclear medicine and radiology services are provided. Use of PET to directly visualize metabolic changes occurring in the brains of those undergoing evaluation for early dementia can thus contribute significantly to the assessment of patients with cognitive symptoms seen in routine clinical settings.

FUTURE DIAGNOSTIC AND THERAPEUTIC STRATEGIES

The longitudinal findings of significant regional metabolic decline in posterior cingulate, parietal, temporal, and other brain regions involved in cognitive functioning in asymptomatic persons at genetic risk for AD have now been confirmed at several centers in separate subject cohorts. ^31,33 Such results indicate that combining PET imaging of glucose metabolism and genetic risk may be useful outcome markers in AD prevention trials. The major genetic risk for AD, the apolipoprotein E-4 (APOE-4) allele has proved most useful to date, but when additional genetic risks are identified, this strategy will become even more effective. Functional brain imaging techniques could be used to track preclinical cognitive decline and test candidate prevention therapies without having to perform prolonged multi-site studies using incipient AD as the primary outcome measure. The consistency and extent of the metabolic decline in these well-screened populations indicate that the PET measures provide adequate power to observe such decline in relatively small subject groups. The patterns for regional metabolic decline are similar in APOE-4 non-carriers but less dramatic, so larger sample sizes are needed to detect treatment effects. ³³

These observations provide an opportunity for presymptomatic treatment trials not previously available. Until now, such trials involved studies of preclinical subjects with more severe memory impairments consistent with mild cognitive impairment (MCI), wherein approximately half of subjects actually develop dementia over a 4-year period. The MCI trials have required hundreds of subjects for adequate power. These trials use a categorical variable, incipient dementia, as the primary outcome measure. The introduction of FDG-PET imaging, combined with APOE-4 genetic risk, increases efficiency and reduces costs by addressing the research questions with fewer subjects. Investigators at our institution have already begun two such placebo-controlled trials, one using cyclooxygenase-2 inhibitor drug and the other using a cholinesterase inhibitor drug.

Another promising diagnostic and therapeutic strategy involves the use of new small-molecule probes in conjunction with PET to provide a signal for the accumulation of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of AD. ³⁴ This approach may eventually provide additional diagnostic accuracy, but more immediately it could prove useful in monitoring treatment in trials of new drugs designed to prevent accumulation of plaques and tangles (a current focus of AD drug development) and, more generally, as a surrogate marker with which to track neuropathologic progression of AD.

Insurance Coverage for PET Indications

PRIVATE PAYERS

* Facility should get pre-authorization on all PET studies for patients insured by private payers

* Private payers may be billed (and payment can be received for any PET procedure) using CPT codes.

* ICD-9 codes should be included for efficient claims processing

* CPT codes may not be used for Medicare Claims

MEDICARE

At the date of this printing, Medicare does not cover PET imaging for the evaluation of Alzheimer's disease.

Supported by an unrestricted educational grant from CTI Molecular Imaging, Inc. and PETNET

Applications in PET is published by Anderson Publishing, Ltd., 1301 West Park Ave., Ocean, NJ 07712; (732) 695-0600. O. Oliver Anderson, Publisher, Elizabeth A. McDonald, Managing Editor; Karen King, Art Director

Sponsored by a grant from CTI Molecular Imaging, Inc. The views and opinions expressed in this publication are those of the authors and do not necessarily reflect those of the publisher or sponsor. Full and complete prescribing information should be reviewed regarding any product mentioned prior to use.

©2003 Anderson Publishing, Ltd.