OtherContinuing Education

Brain 18F-FDG PET in the Diagnosis of Neurodegenerative Dementias: Comparison with Perfusion SPECT and with Clinical Evaluations Lacking Nuclear Imaging

Daniel H.S. Silverman
Journal of Nuclear Medicine April 2004, 45 (4) 594-607;

Abstract

The clinical identification and differential diagnosis of dementias is especially challenging in the early stages, but the need for early, accurate diagnosis has become more important, now that several medications for the treatment of mild to moderate Alzheimer’s disease (AD) are available. Many neurodegenerative diseases produce significant brain-function alterations detectable with PET or SPECT even when structural images with CT or MRI reveal no specific abnormalities. 18F-FDG PET images of AD demonstrate focally decreased cerebral metabolism involving especially the posterior cingulate and neocortical association cortices, while largely sparing the basal ganglia, thalamus, cerebellum, and cortex mediating primary sensory and motor functions. Assessment of the precise diagnostic accuracy of PET had until recently been hindered by the paucity of data on diagnoses made using PET and confirmed by definitive histopathologic examination. In the past few years, however, studies comparing neuropathologic examination with PET have established reliable and consistent accuracy for diagnostic evaluations using PET—accuracies substantially exceeding those of comparable studies of the diagnostic value of SPECT or of both modalities assessed side by side, or of clinical evaluations done without nuclear imaging. Similar data are emerging concerning the prognostic value of 18F-FDG PET. Improvements in the ability of PET to identify very early changes associated with AD and other neurodegenerative dementias are currently outpacing improvements in therapeutic options, but with advances in potential preventive and disease-modifying treatments appearing imminent, early detection and diagnosis will play an increasing role in the management of dementing illness.

Alzheimer’s disease (AD) is the leading neurodegenerative disorder and accounts for approximately two thirds of cases of dementia. AD currently affects 4 million people in the United States and is estimated to eventually affect 14 million as the aging of the baby boomers expands our geriatric population (1–3).

Advances in therapeutic agents for the treatment of AD have progressed substantially in the past decade. Cholinesterase inhibitors have successfully been used for a decade to delay cognitive decline associated with mild to moderate disease, and memantine was approved by the U.S. Food and Drug Administration last year for treating patients with more advanced AD. Similarly, neuroimaging techniques, including SPECT and PET, used in the evaluation and early detection of the disease have improved considerably.

AD can be diagnosed definitively only by histopathologic examination of brain tissue (4). The identification and differential diagnosis of AD is especially challenging in its early stages, partly because of the difficulty in distinguishing it from the mild decline in memory that can occur with normal aging and from mild cognitive manifestations of other neuropsychiatric conditions, such as depression, as well as other causes of dementia. Physicians frequently err both by failing to make the diagnosis of AD when the disease is present and by diagnosing early AD when it is absent (5–8). Moreover, clinical assessment frequently involves multiple examinations and laboratory tests over months or years.

The need for early, accurate diagnosis has become more important, now that several medications for the treatment of mild to moderate AD are available. Patients with neurodegenerative disease have the most to gain from therapy that intervenes as early as possible in the course of inexorably progressive, irreversible damage to brain tissue, and controlled clinical trials have demonstrated that cholinesterase inhibitors can improve, or delay decline in, memory and other cognitive functions in mild or moderately affected AD patients (9–15). These treatments can cut by more than half the proportion of patients requiring nursing home placement over a given time (16,17). Cholinergic (and other (18)) agents also are beneficial through reducing behavioral problems, improving patients’ functional abilities, and decreasing caregiver burden (13,19–22). Studies examining long-term effects of cholinesterase inhibitors indicate that drug treatment delays cognitive decline in AD patients by 9–12 mo on average and delays the need for institutionalization by 18 mo on average (19,23–25). Moreover, delaying the implementation of therapy by as little as 6 mo—besides carrying the inherent adverse consequence of depriving the patient of the short-term advantages of potentially enhanced cognitive and functional abilities during that time—may have long-term consequences as well (13,19,26). In a randomized, placebo-controlled trial of the cholinesterase inhibitor galantamine in patients with mild to moderate AD, Raskind et al. (13) found that the drug significantly improved cognitive function relative to placebo after 6 mo of treatment; during an ensuing 6-mo open-label treatment period, the patients who were originally in the placebo group were also given galantamine. At 1 y, better cognitive performance was seen in patients who began drug treatment at the beginning of the trial than in those whose treatment had been delayed for 6 mo. Similar benefits have also resulted from earlier institution of therapy with either rivastigmine (11) or donepezil (26). If functional neuroimaging is indicated for a particular patient, performing it within 6 mo of identifying progressive cognitive decline that could represent incipient AD would be prudent.

LIMITATIONS OF CONVENTIONAL CLINICAL EVALUATION

Few studies have specifically addressed the question of clinical detection of very mild disease, particularly in comparison with the standard criterion of histopathologic diagnosis. In an investigation aimed at doing so, patients who initially appeared healthy or minimally affected were followed up with repeated examinations for an average of 4 y (27). Even by the end of this longitudinal follow-up period, a neurologist detected AD in only 70% of the patients who were histologically positive for AD. In the recent report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN) (28), the source of the most comprehensive guidelines and standards for the clinical evaluation of dementia in the last several years, 3 class I studies (7,29,30) were identified in which the diagnostic value of clinical assessment could meaningfully be measured. 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.” Only one of them (7) focused on evaluating dementia at a relatively early stage. To be included in that investigation, patients were required to have had an onset of dementia symptoms within 1 y of entry. All 134 patients evaluated underwent a complete standardized diagnostic work-up comprising comprehensive medical history, physical examination, neurologic examination, neuropsychologic testing, laboratory testing, and structural neuroimaging and an average of 3 additional years of clinical follow-up with repeated testing. Sensitivity of this assessment for AD was 83%–85%, whereas specificity was 50%–55%, yielding an overall accuracy of 69%. In these studies, and in most similar studies, the reported sensitivities and specificities represent not the diagnostic accuracy of an initial clinical evaluation but the diagnostic accuracy of an entire series of evaluations repeated over a period of years.

When neuroimaging is performed in the evaluation of dementia, patients are usually referred for a structural imaging examination—that is, MRI or CT. 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 (28). However, in patients with AD (which is much more common), such scans are typically read as showing normal findings, as demonstrating the nonspecific finding of cortical atrophy, or as revealing ischemic changes that are (mis)interpreted as pointing to cerebrovascular disease as the primary or sole cause of the patient’s cognitive decline. The result could be failure to institute appropriate, timely pharmacotherapy (e.g., donepezil, rivastigmine, or galantamine, which are approved 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. In a multicenter study involving 7 university-affiliated AD Diagnostic and Treatment Centers, among patients in whom “vascular dementia” was diagnosed after clinical and structural neuroimaging evaluations and in whom other dementia diagnoses were specifically thought to be absent, fewer than 30% actually had isolated cerebrovascular disease, and the majority (55%) had AD on pathologic diagnosis (31).

NEURONUCLEAR IMAGING IN DEMENTIA ASSESSMENT

Over the last 2 decades, clinicians and researchers have obtained substantial experience in using the 3-dimensional imaging capabilities of PET and SPECT for the identification and differential diagnosis of dementia (32–34). Thousands of patients with clinically diagnosed and, in some cases, histopathologically confirmed AD from many independent laboratories have been studied using measures of cerebral blood flow, glucose metabolism, or oxygen use obtained through these tomographic neuronuclear imaging modalities. The principal findings from that experience briefly are as follows: A consistent pattern of focally decreased cerebral metabolism and perfusion has been identified, involving especially the posterior cingulate and neocortical association cortices but largely sparing the basal ganglia, thalamus, cerebellum, and cortex mediating primary sensory and motor functions. Most studies also reported greater sensitivity to disease severity for the parietal lobe deficit than for the temporal lobe deficit. Frontal lobe hypoperfusion was also often reported, but not in the absence of temporoparietal abnormalities. A pattern of focal cortical inhomogeneities, all accounted for by areas of infarction on MRI, implies dementia secondary to cerebrovascular disease, which also often affects cerebellum and subcortical structures. A pattern of focal cortical inhomogeneities unmatched by MRI findings is consistent with a primary neurodegenerative disorder (e.g., AD, Pick’s disease, other frontotemporal dementia, dementia with Lewy bodies, dementia of Parkinson’s disease, Huntington’s disease, or progressive subcortical gliosis.) As a rule, the pattern of bilateral temporoparietal hypoperfusion or hypometabolism well discriminates AD patients not only from age-matched healthy controls but also from patients with vascular dementia or frontal lobe dementia. However, more overlap of that pattern has been observed in patients with Lewy body dementia, Creutzfeldt–Jakob disease, and Parkinson’s disease with dementia (Table 1). Neuronuclear imaging abnormalities correlate not only with dementia severity and specific patterns of cognitive failure in AD patients but also with regional densities of neurofibrillary tangles (35).

View this table:
TABLE 1

Imaging Findings Pertaining to Differential Diagnosis of Dementias

RECENT STUDIES ON PET ACCURACY IN DEMENTIA EVALUATION

Diagnosis

Clinical applications of neuronuclear imaging in dementia patients stem from numerous studies that have found many neurodegenerative diseases to produce significant alterations in brain function detectable with SPECT or PET even when structural images with CT or MRI reveal no abnormality. The utility of PET in this regard has been under study since the early 1980s (36–39) and has been extensively reviewed more recently (40–45).

Thousands of patients with clinically diagnosed—and, in some cases, histopathologically confirmed—causes of dementia from many independent laboratories have been studied using PET measures of cerebral blood flow, glucose metabolism, or oxygen use. The best-studied application of this type is the use of 18F-FDG PET to evaluate AD. Table 2 presents published studies that assessed the diagnostic value of PET in the evaluation of dementia. The typically high sensitivity of 18F-FDG PET, even in patients with mild impairment, suggests that by the time a patient presents with symptoms of a neurodegenerative dementia, substantial alteration of cortical metabolic function generally has occurred. The associated decreases in glucose metabolism in certain brain areas are readily detectable on 18F-FDG images. Some visually evident differences between scans of patients with different dementing illnesses are seen in Figures 1–7.

FIGURE 1.
FIGURE 1.

Normal adult pattern of cerebral glucose metabolism measured with 18F-FDG. Images are shown from the most superior (far left column) to most inferior (far right column) planes of the brain. In this and later figures, images are cross-sectional and are displayed with the anterior brain at the top of each image and the left side of the brain on the right of each image. Normal aging is associated with some increased generalized cortical atrophy, as evidenced by moderate widening (arrow) of the interthalamic distances in the 85-y-old patient (middle right). Additional arrows highlight the progression of mild metabolic decline, also attributable to normal aging, in the medial prefrontal cortex bilaterally (middle left, ages 53 and 85 y) and in the left anterior prefrontal cortex (middle left, age 85 y). Otherwise, in healthy adults, the pattern of regional cerebral metabolism changes little throughout adulthood.

FIGURE 2.
FIGURE 2.

18F-FDG PET images of early AD. Early Alzheimer’s typically affects the parietal, temporal, and posterior cingulate cortices. Brain images of this 80-y-old woman demonstrate hypometabolism of the parietal cortex, bilaterally (left and middle), with relative sparing of the primary visual cortex, sensorimotor cortex, thalamus, and basal ganglia. In the early stages of AD, deficits often appear asymmetrically, as evidenced here by mild hypometabolism of the left temporal cortex (right). In later stages of the disease, degeneration will be apparent bilaterally.

FIGURE 3.
FIGURE 3.

18F-FDG PET images of early- and late-stage dementia with Lewy bodies. Typical cerebral metabolic patterns for patients with dementia with Lewy body disease are similar to AD patterns, but with less sparing of the occipital cortex. A patient with early-stage disease (top row; 63-y-old woman) was clinically followed up for 28 mo, during which her MMSE score dropped from 23 to 14, of 30 possible points. The arrows on her scan highlight bilateral hypometabolism of the parietal (left) and occipital (middle) cortices, as well as hypometabolism of the posterior temporal cortex (right). A patient in a later stage of the disease (bottom row; 71-y-old man) has moderate to severe bilateral hypometabolism in the parietal cortex (left) and in the temporooccipital cortex (right), as similarly seen in the early-stage patient. Additional arrows in the left image refer to progression of hypometabolism in the occipital and prefrontal cortices, bilaterally.

FIGURE 4.
FIGURE 4.

18F-FDG PET images of Parkinson’s disease dementia. Typical patterns of regional cerebral metabolism are similar in Parkinson’s dementia and AD, with less sparing of the occipital cortex and more sparing of the mesiotemporal area. The diagnosis of Parkinson’s disease in this patient (72-y-old woman) was subsequently confirmed by autopsy. The arrows on her scan indicate parietal (left and middle images) and occipital (middle and right images) hypometabolism, whereas the 18F-FDG uptake in basal ganglia is undiminished at this stage of her disease.

FIGURE 5.
FIGURE 5.

18F-FDG PET images of vascular dementia. Hypometabolism affecting cortical, subcortical, and cerebellar areas is often seen in vascular dementia. This patient (65-y-old woman) was followed for 10 mo, and vascular dementia was diagnosed both clinically and by structural imaging. Arrows indicate hypometabolism of the right frontal cortex (far left, middle right), right parietal cortex (far left, middle left), right basal ganglia and thalamus (middle right), and right temporal cortex (far right). The hypometabolism of the left cerebellum (far right) is characteristic of cross-cerebellar diaschisis, caused by diminished afferent input from the contralateral cortex.

FIGURE 6.
FIGURE 6.

18F-FDG PET images of early frontotemporal dementia. This patient (66-y-old man) was diagnosed both clinically and by PET as having frontotemporal disease. The patient’s MMSE score at the time of PET was 27 of a possible 30 points. Arrows indicate bilateral hypometabolism of the frontal cortex (far left), at a time that the remainder of the cerebral activity is not appreciably affected (middle left, middle right, and far right).

FIGURE 7.
FIGURE 7.

18F-FDG PET images of Huntington’s disease. This patient (43-y-old man) has an 8-y history of progressive Huntington’s disease. Arrows highlight the typical metabolic pattern of hypometabolism severely affecting the basal ganglia (right) at a time that cortical metabolism is still relatively intact (left and middle). As the disease progresses, diffuse cortical involvement gradually develops.

View this table:
TABLE 2

Use of PET for Differential Diagnosis of AD

Assessment of the diagnostic accuracy of PET had until recently been hindered by the paucity of studies involving patients who were followed up long term or for whom subsequent pathologic diagnosis was available; most previous clinical series compared PET findings with clinical assessments performed near the time of PET. The ability of the latter approach to assess diagnostic accuracy is unfortunately limited by the potential inaccuracy of clinical diagnosis, particularly for patients presenting in the earliest stages of disease—a time when the opportunity for effective therapy, and for meaningful planning, is greatest.

Studies comparing neuropathologic examination with imaging are thus most informative in assessing the diagnostic value of PET. In a pooled analysis (44) of 3 previously published studies (46–48), the histopathologically confirmed sensitivity and specificity of PET for detecting the presence of AD were 92% and 71%, respectively. In the largest single-institution series, Hoffman et al. (49) found the sensitivity and specificity of PET for AD to fall in the range of 88%–93% and 63%–67%, respectively. A subsequent multicenter study collected data from an international consortium of clinical facilities that had acquired both 18F-FDG PET and histopathologic brain data for patients undergoing evaluation for dementia (50). The PET results identified AD patients with a sensitivity and specificity of 94% and 73%, respectively. This last study, which had more than 3 times as many patients as did the 4 previous studies combined, included a stratified examination of the subset of patients with documented early or mild disease. The performance of PET with respect to sensitivity (95%), specificity (71%), and overall accuracy (89%) was unaltered. These values agree with the ranges found in a broader literature review of PET studies, including those lacking neuropathologic confirmation of diagnoses (51). That review found reported sensitivities ranging from 90% to 96% and specificities ranging from 67% to 97%. The values also agree with a recent review of the PET literature reported by the AAN (28), which concluded that “PET scanning appears to have promise for use as an adjunct to clinical diagnosis [of AD],” based on its review of published studies that demonstrated diagnostic accuracies of 86%–100% for PET.

Regional cerebral metabolic changes associated with early AD can be detected with PET even before the symptomatic manifestations of the disease become evident (50,52,53). How accurate can 18F-FDG PET be in the evaluation of nondemented patients, who are in the earliest stages of cognitive impairment? Table 3 reviews the most recent 18F-FDG PET neuroimaging studies involving patients classified as cognitively impaired nondemented or having mild cognitive impairment. The studies were conducted or published between 2001 and 2003 and were found by searching PubMed in July 2003 (keywords: PET, cognitively impaired not demented, mild cognitive impairment) and by systematically checking the bibliographies of relevant articles so identified. The major criterion for inclusion was the use of 18F-FDG PET to evaluate cognitively impaired nondemented patients or patients with mild cognitive impairment as a specific subject subset in the study; investigations that did not involve 18F-FDG PET were excluded. Overall accuracies achieved with 18F-FDG PET have been nearly as high in very mildly affected patients as in demented patients, generally exceeding 80% and ranging from 75% to 100%, in these recent studies. PET may be especially valuable in this clinical setting, considering the difficulty of distinguishing these patients from those with mild memory loss attributed to normal aging.

View this table:
TABLE 3

18F-FDG PET in the Evaluation of Nondemented Subjects (Cognitively Unimpaired or Mildly Impaired)

Prognosis

18F-FDG PET may also serve explicitly as a prognostic tool, to determine likelihood of deterioration of mental status during the time after scanning. Relative hypometabolism of associative cortex can accurately predict whether cognitive decline will occur more quickly than would be expected for normal aging during the first several years after a PET evaluation (52,54). Moreover, the magnitude of decline during 2 y, for some standardized measures of memory, correlates with the initial degree of hypometabolism of inferior parietal, superior temporal, and posterior cingulate cortical regions (55). As cognitive impairment caused by neurodegenerative disease progresses, associated progression of regions of hypometabolism also occurs.

In a longitudinal evaluation of 170 patients who underwent brain PET, analyses were stratified according to presence of the most common comorbidities affecting cognitive function (other than primary neurodegenerative disease)—depression and thyroid disease—and according to scanner type (56). At the time of PET, more than one third (65/170, or 38%) of all patients were documented to have had a history of depression; 18%, a history of thyroid disease; and 6%, a history of both. PET findings accurately predicted, with a sensitivity of 91% (99/109), which patients would have a subsequent progressive course. Patients having a subsequent nonprogressive course were identified with a specificity of 80% (49/61). Of the patients without a history of depression or thyroid disease, the specificity of PET was nearly as high as its sensitivity (89%, with a 95% confidence interval [CI] of 77%–100%), but the specificity tended to be lower for patients with a history of depression or thyroid disease (74%, with a 95% CI of 59%–88%) than in those without either condition. In contrast, sensitivity was unaffected by the presence of those conditions (90%, with a 95% CI of 82%–98%, vs. 92%, with a 95% CI of 84%–100%). Although the prognosis of most subjects was correctly predicted by visual analysis of PET scans regardless of the presence of depression or thyroid disease, specificity tended to be lower for patients with a history of those conditions, and the overall false-positive rate of PET used in the prediction of a clinically progressive course of dementia was 3 times higher (3.5% [3/86] vs. 10.7% [9/84]) in patients with a history of depression or thyroid disease. It is thus suggested that physicians interpret positive brain scan findings with added caution when determining the prognosis for dementia in cognitively impaired patients with depression or thyroid disease, because of the potentially confounding effects of those conditions on regional brain metabolism (Figs. 8 and 9). What is also of clinical pertinence is that, because data were collected for almost a decade, scanner types changed during that time (e.g., brain PET conducted on the older generation of scanners contained only 15 planes, whereas scans obtained on the newer generation of scanners contained either 47 or 63 planes), and specificity tended to be higher for scans obtained on the newer generation of scanners (87%, with a 95% CI of 73%–100%, vs. 76%, with a 95% CI of 63%–90%).

FIGURE 8.
FIGURE 8.

Distribution of 111 scan-positive cases among 170 patients undergoing PET for cognitive evaluation. TP = true positives; FP = false positives.

FIGURE 9.
FIGURE 9.

18F-FDG PET scans of a patient with false-positive findings and an AD patient. Shown are representative axial (left) and sagittal (middle) slices through an 18F-FDG PET brain scan of a 79-y-old woman undergoing clinical evaluation for cognitive impairment. The patient had a history of depression and thyroid disease and was receiving thyroid hormone replacement therapy at time of PET. The interpreting nuclear medicine physician had read the scan as consistent with early neurodegenerative changes in an Alzheimer-like pattern, because of the apparent relative decreased activity in the parietal cortex (bold white arrows), relative to the adjacent frontal and temporal cortex (thin white arrows). Longitudinal clinical follow-up for 2.5 y after the scan showed no progressive dementia, so the scan interpretation was classified as false positive. If this scan were being read now, the false-positive interpretation might have been avoided by comparing the thalamic activity (red arrows) to the parietal activity, with which it is approximately isometabolic, and to the (higher) frontal activity—in contrast to the pattern found in AD (right), in which parietal cortex becomes hypometabolic relative to the (preserved and normally isometabolic) thalamus.

It is interesting to consider the mechanistic basis that may underlie at least some of the false-positive associations. Bench et al. (57) reported that metabolism of certain cerebral regions correlates negatively with mood symptoms and severity of psychomotor slowing in depression; these regions included the inferior parietal and superior temporal cortex, areas also affected in AD. Effects of hypothyroidism on regional cerebral metabolism have also recently been described (58,59), involving relative reduction in parietal and temporal metabolism. These effects may further help explain the compromise in PET specificity associated with such conditions, particularly with older scanners lacking the resolution to distinguish characteristic patterns of regional involvement from similar but distinct regions.

With respect to the incremental value of PET beyond conventional clinical assessment, it was recently found that among patients having clinical working diagnoses presuming nonprogressive etiologies for their cognitive complaints, those whose PET patterns nevertheless indicated progressive dementia were more than 18 times more likely to experience progressive decline than were those with nonprogressive PET patterns (54). Neurologists who diagnosed progressive dementia in their patients were correct 84% of the time. Adding a positive diagnosis from a PET scan boosted the accuracy of that prediction to 94%, and negative PET findings made it 12 times more likely that the patient would remain cognitively stable.

COMPARISONS BETWEEN SPECT AND PET

SPECT has historically been the most widely available modality for functional imaging of the brain and thus became the one most commonly used in the clinical evaluation of dementia (60). Most of the clinical and research SPECT studies for this application have been perfusion based. Although the specific radiopharmaceuticals and instrumentation used in SPECT differ from those used in PET, the principles of interpretation, as well as the neurobiologic processes underlying the use of the 2 modalities, are similar. The primary practical differences in application are, first, the typically poorer spatial resolution of SPECT images relative to that of PET images and, second, the occasional loss of the generally parallel relationship between cortical metabolism (usually measured with PET) and perfusion in the presence of certain cerebrovascular disorders. In general, the magnitude of hypometabolism seen with 18F-FDG PET is generally greater than the amplitude of hypoperfusion seen with SPECT (61–63).

As might be expected, studies of AD using SPECT have yielded results similar to those using PET but typically with less sensitivity and decreased overall accuracy. Optima (Oxford Project to Investigate Memory in Aging) was a relatively large study that compared functional brain imaging data (SPECT regional cerebral blood flow) against clinical diagnosis and, in the dementia subset, autopsy diagnosis. The study included 70 dementia patients (all of whom had autopsy data) and 85 nondemented subjects (only 14 of whom had autopsy data) (64). Clinical diagnosis of probable AD was reported to have a 59% sensitivity and a 95% specificity for patients with an autopsy-confirmed diagnosis, and these values increased to 93% and 88%, respectively, for the combination of possible or probable AD. SPECT alone was reported to have a 63% sensitivity and a 93% specificity. The combination of SPECT findings positive for temporoparietal hypoperfusion and a clinical diagnosis of possible or probable AD was associated with a 96% sensitivity and an 84% specificity. These data were acquired with a single-head γ-camera with approximately 12-mm spatial resolution and may represent the lower end of sensitivity measurements possible with state-of-the-art equipment. These authors also used logistic regression analysis to compute the degree to which SPECT enhanced clinical diagnosis. Clinical diagnosis of probable AD alone was associated with an 84% chance of AD on death; positive SPECT findings raised the likelihood to 92%, whereas negative SPECT findings reduced the likelihood to 70%. For the diagnosis of possible AD, clinical measures alone had a 67% likelihood, which increased to 84% with positive SPECT findings and decreased to 52% with negative findings. Therefore, a clinical diagnosis of possible AD combined with a SPECT scan positive for temporoparietal hypoperfusion was as likely to be associated with AD at death as was clinical diagnosis of probable AD alone.

Unfortunately, in this study the nondemented controls were not control subjects in a clinically meaningful sense of the term: the mean Mini-Mental State Examination (MMSE) score for the patients was 13 ± 8 points (of a total of 30 possible points), whereas the mean MMSE of the “controls” was 29 ± 2. Subjects with cognitive performances so discrepant from those of the patient group would easily be distinguishable in clinical practice, even without formal dementia evaluation or functional imaging. Including them in the analysis thus lent a considerable but artificial boost to estimates of specificity and overall accuracy relative to how the test would perform in an actual clinical setting. In addition, the moderately severe degree of mean cognitive impairment of the AD cases may have increased the sensitivity estimates. Moreover, because 71 of the 85 control subjects were not autopsied, for the majority of non-AD cases clinical diagnosis was being compared with a gold standard of clinical diagnosis—a tautology that provided another artificial boost to specificity and overall accuracy. These problems are largely avoided, however, if the analysis is confined to the (autopsy-proven) dementia cases. Among those 70 patients, at a clinical diagnostic sensitivity for AD of 93% (43/46) (achieved by pooling both probable-AD and possible-AD patients), clinical specificity was 46% (11/24). Also among those cases, the sensitivity of SPECT for AD was 63% (29/46) and specificity was 75% (18/24), for an overall accuracy of 67% (47/70).

The higher diagnostic accuracy achievable with PET than with SPECT has been further borne out through side-by-side comparisons of the 2 modalities. These comparisons include studies using high-resolution SPECT scanners (34,66) on AD patients with mild symptoms (65), with data suggesting an increased accuracy of approximately 15%–20% for PET relative to SPECT. When considering the results of these types of comparative studies, it is worth noting that the utility of both PET and SPECT can be influenced by factors such as the spatial resolution and count sensitivity of detector configurations and by other instrumentation parameters, acquisition and processing techniques, methods and quality of image display, the interpretive criteria used, and the experience of the interpreters with each modality. In a recent study minimizing the impact of at least one (the last) of these factors, Herholz et al. (67) compared the ability of PET and SPECT to identify abnormalities in AD subjects, using statistical parametric mapping to assess the number of abnormal voxels relative to an age-matched control group for each technique. The best correspondence was in the temporoparietal and posterior cingulate cortices (r = 0.90). However, tracer uptake reductions were significantly more pronounced with PET than with SPECT. Herholz et al. also measured the correlation between dementia severity and the number of abnormal voxels. That correlation was somewhat better for PET than for SPECT. The higher sensitivity of PET may be especially relevant for identifying disease in its earliest stages to target patients for therapy while neurodegeneration is minimal.

CLINICAL ROLE OF NEURONUCLEAR IMAGING

As previously mentioned, in the recent report of the Quality Standards Subcommittee of the AAN (28), 3 studies (7,29,30) were identified in which the diagnostic value of conventional clinical assessment could be measured well (Table 4). If one accepts the recently affirmed AAN recommendation (28) that the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)-Alzheimers Disease and Related Disorders Association (ADRDA) criteria for “probable AD [rather than the more inclusive ‘possible AD’] should be routinely used,” then clinical sensitivity appears to range in the interval of 66% ± 17%, whereas PET sensitivity ranges in the interval of 91.5% ± 3.5%, relative to the standard criterion of neuropathologically confirmed diagnosis (Table 5). The sensitivity of clinical evaluation can be increased to 90.5% ± 5.5% (comparable to that using PET), but at the expense of specificity (55.5% ± 5.5% in the class I studies), by expanding the diagnosis of AD to include patients who meet NINCDS-ADRDA criteria for “possible AD” and including moderately and severely advanced dementia cases in the analysis. In contrast, at that level of sensitivity, the specificity using PET is 70% ± 3%. The AAN Quality Standards Subcommittee also reviewed 9 studies that addressed the clinical diagnostic accuracy of AD but were classified as having lower “quality of evidence.” Across all these studies, they found an average clinical specificity of 70% (as occurs with PET), whereas average sensitivity in that analysis was 81% (compared with the 91% ± 3% reported for PET). In the 2 largest class II studies that uniformly used NINCDS-ADRDA diagnostic criteria (31,68), at a sensitivity of 90% ± 1% (achieved by including “possible AD” patients and moderately advanced dementia cases), specificity fell to 29% ± 8%.

View this table:
TABLE 4

Sensitivity and Specificity of Conventional Clinical Evaluation, Compared with Neuropathologic Confirmation of Presence or Absence of AD

View this table:
TABLE 5

Ranges of Sensitivity and Specificity of Clinical Diagnoses Made With and Without the Use of PET, Compared with Neuropathologic Confirmation of Presence or Absence of AD

Thus, when the most reliable published measures of sensitivity and specificity in the diagnosis of AD (7,28–30) are applied to a comparison of diagnoses made with PET and diagnoses made without PET, one finds that both false-negative and false-positive diagnoses may substantially be decreased by adding PET to the diagnostic work-up of appropriately selected patients (69).

The available evidence supports considering PET for at least 2 groups of patients: patients with mild or moderate cognitive impairment who meet the standard criteria for dementia, the cause of which has not been identified by an appropriate and thorough medical work-up (group A; Table 6), or patients with mild or moderate cognitive impairment who exhibit progressive cognitive dysfunction that has not reversed after a thorough medical work-up including history taking, physical examination, neurologic examination, and indicated standard laboratory and structural neuroimaging tests along with appropriate treatment for any positive findings (group B; Table 7).

View this table:
TABLE 6

Impact of Diagnostic Accuracy Achievable with Use of PET, for Patients in Group A (Mild or Moderate Dementia of Unclear Etiology)

View this table:
TABLE 7

Impact of Diagnostic Accuracy Achievable with Use of PET, for Patients in Group B (Progressive Cognitive Decline That All Attempted Treatments Have Failed to Reverse)

For each of these 2 patient groups, the respective tables indicate the impact of the diagnostic accuracy achievable when PET is included as part of the medical work-up, relative to when it is not included. The high sensitivity of PET may be especially useful in identifying progressive dementia among those for whom suspicion of a progressive dementing illness is otherwise low; appropriate therapy to delay decline can then be started earlier. The best time to perform functional neuroimaging is thus early in the clinical work-up, as soon as the appropriateness of including neuroimaging in the evaluation of cerebrocortical dysfunction has been determined (69).

THE FUTURE

Although AD has no cure, symptomatic treatment has proven effective, especially in earlier stages of the disease, and therapies targeting etiology-based treatments are in development. Possible etiology-targeting cures in the future would be most effective during the milder phases of the disease, making an early clinical diagnosis of AD, when treatment can alter the progression of symptoms, especially important. Progress in understanding of the etiology of AD will lead to new and more effective methods of treatment.

Studies examining combination treatments are limited. Combining current treatments such as anticholinesterase inhibitors with other interventions may further improve the management of AD. For example, the proven benefits of the psychosocial intervention studied by Mittelman et al. (70) may be made more dramatic by combining it with anticholinesterase therapy, and studies of the combination of cholinesterase inhibitors with other agents such as memantine or vitamin E are under way. As more studies examine the combined effects of currently available treatments, a better understanding of multimodal treatment plans will emerge.

Current studies targeting earlier processes in the pathophysiologic changes of AD show potential for new treatment approaches. Rinne et al. (71) recently determined that acetylcholinesterase activity in the hippocampus differs significantly between control patients, patients with mild cognitive impairment, and patients with early AD. The ability to detect these differences may allow patients requiring therapeutic intervention to be identified early, before the onset of clinical symptoms. Other studies have focused on the amyloid precursor protein-cleaving enzyme responsible for β-site cleavage of amyloid precursor peptide, leading to formation of the amyloid-β-peptide implicated in the pathogenesis of AD (72). Inhibitors of this enzyme may potentially be applied for future therapeutic interventions for AD.

As our understanding of the biology of AD increases, we will be able to target future treatment options toward patients in those disease stages for which treatment is most appropriate and beneficial. Currently, the categorization of patients with memory deficits such as mild cognitive impairment and age-associated memory impairment is not universal. Although categorization is not uniform between different groups, the opportunity is arising to sort out and create categories that are more meaningful with regard to the underlying biology of the disease process, as made possible with diagnostic approaches such as 18F-FDG PET.

The biologic changes that occur with AD take place decades before the onset of clinical symptoms. Use of more powerful diagnostic approaches allows earlier detection of initial changes in a target population, before AD is diagnosed. Currently, tools for identifying the early changes of AD are outpacing available therapeutic options. With advances in potential disease-modifying treatments, the benefits of early detection will be even greater by allowing therapy to begin as early as possible.

Footnotes

  • Received Jan. 28, 2004; revision accepted Feb. 11, 2004.

    For correspondence or reprints contact: Daniel H.S. Silverman, MD, PhD, Ahmanson Biological Imaging Division, UCLA Medical Center, CHS AR-144, MC694215, Los Angeles, CA 90095-6942.

    E-mail: dsilver{at}ucla.edu

  • ↵* NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH THE SNM WEB SITE (http://www.snm.org/education/ce_online.html) THROUGH APRIL 2005.

REFERENCES

  1. ↵
    Koppel R. Alzheimer’s Disease: The Costs to U. S. Businesses in 2002. Washington D.C.: Alzheimer’s Association; 2002.
  2. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA. 1997;278:1363–1371.
    OpenUrlCrossRefPubMed
  3. ↵
    Bachman DL, Wolf PA, Linn RT, et al. Incidence of dementia and probable AD in a general population: the Framingham study. Neurology. 1993;43:515–519.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of AD: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services task force on AD. Neurology. 1984;34:939–944.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Callahan CM, Hendrie HC, Tierney WM. Documentation and evaluation of cognitive impairment in elderly primary care patients. Ann Intern Med. 1995;122:422–429.
    OpenUrlCrossRefPubMed
  6. Hoffman RS. Diagnostic errors in the evaluation of behavioral disorders. JAMA. 1982;248:964–967.
    OpenUrlCrossRefPubMed
  7. ↵
    Lim A, Tsuang D, Kukull W, et al. Clinico-neuropathological correlation of AD in a community-based case series. J Am Geriatr Soc. 1999;47:564–569.
    OpenUrlPubMed
  8. ↵
    McDaniel LD, Lukovits T, McDaniel KD. AD: the problem of incorrect clinical diagnosis. J Geriatr Psychiatry Neurol. 1993;6:230–234.
  9. ↵
    Birks J, Iakovidou V, Tsolaki M. Rivastigmine for AD: Cochrane database systemic review. In: The Cochrane Library. Oxford, U.K.: Update Software Ltd.; 2000;4:CD001191.
    OpenUrl
  10. Burns A, Rossor M, Hecker J, et al., and the International Donepezil Study Group. The effects of donepezil in AD: results from a multinational trial. Dementia. 1999;10:237–244.
  11. ↵
    Corey-Bloom J, Anand R, Veach J, for the ENA 713 B352 Study Group. A randomized trial evaluating the efficacy and safety of ENA 713 rivastigmine tartrate, a new acetylcholinesterase inhibitor, in patients with mild to moderately severe AD. Int J Geriatr Psychopharmacol. 1998;1:55–65.
    OpenUrl
  12. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with AD. The Tacrine Study Group. JAMA. 1994;271:985–991.
    OpenUrlCrossRefPubMed
  13. ↵
    Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2261–2268.
    OpenUrlAbstract/FREE Full Text
  14. Rogers SL, Friedhoff LT, Apter JT, et al. The efficacy and safety of donepezil in patients with AD: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia. 1996;7:293–303.
  15. ↵
    Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with AD: international randomized controlled trial. Br Med J. 1999;318:633–638.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Knopman D, Schneider LS, Davis K, et al. Long-term tacrine (Cognex) treatment effects on nursing home placement and mortality. The Tacrine Study Group. Neurology. 1996;47:166–177.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Small GW, Donohue JA, Brooks RL. An economic evaluation of donepezil in the treatment of AD. Clin Ther. 1998;20:838–850.
    OpenUrlCrossRefPubMed
  18. ↵
    Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for AD. N Engl J Med. 1997;336:1216–1222.
    OpenUrlCrossRefPubMed
  19. ↵
    Coyle J, Kershaw P. Galantamine, a cholinesterase inhibitor that allosterically modulates nicotinic receptors: effects on the course of AD. Biol Psychiatry. 2001;49:289–299.
    OpenUrlCrossRefPubMed
  20. Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioral, and global function in patients with AD. Neurology. 1998;50:1222–1230.
    OpenUrlAbstract/FREE Full Text
  21. Tariot P, Solomon P, Morris J, et al., and the Galantamine Study Group. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology. 2000:54;2269–2276.
  22. ↵
    Weiner MF, Martin-Cook K, Foster BM, Saine K, Fontaine CS, Svetlik DA. Effects of donepezil on emotional/behavioral symptoms in AD patients. J Clin Psychiatry. 2000;61:487–492.
    OpenUrlPubMed
  23. ↵
    Fago JP. Dementia: causes, evaluation, and management. Hosp Pract (Off Ed). 2001;36:59–69.
    OpenUrlPubMed
  24. Imbimbo BP, Verdelli G, Martelli P, Marchesini D. Two-year treatment of AD with eptastigmine. Dement Geriatr Cogn Disord. 1999;10:139–147.
    OpenUrlCrossRefPubMed
  25. ↵
    Rogers SL, Friedhoff LT. Long-term efficacy and safety of donepezil in the treatment of AD: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol. 1998;8:67–75.
    OpenUrlCrossRefPubMed
  26. ↵
    Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Donepezil Study Group. Arch Neurol. 2001;58:427–433.
    OpenUrlCrossRefPubMed
  27. ↵
    Morris JC, McKell DW, Storandt M, et al. Very mild Alzheimer’s disease: informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology. 1991;41:469–478.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56:1143–1153.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Jobst KA, Barnetson LP, Shepstone BJ. Accurate prediction of histologically confirmed AD and the differential diagnosis of dementia: the use of NINCDS-ADRDA and DSM-III-R criteria, SPECT, x-ray, CT, and apo E4 in medial temporal lobe dementias. Oxford Project to Investigate Memory and Aging. Int Psychogeriatr. 1998;10:271–302.
    OpenUrlCrossRefPubMed
  30. ↵
    Holmes C, Cairns N, Lantos P, et al. Validity of current clinical criteria for AD, vascular dementia and dementia with Lewy bodies. Br J Psychiatr. 1999;174:45–50.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    Victoroff J, Mack WJ, Lyness SA, et al. Multicenter clinicopathological correlation in dementia. Am J Psychiatr. 1995;152:1476–1484.
    OpenUrlPubMed
  32. ↵
    Silverman DHS, Devous MD. PET and SPECT imaging in evaluating Alzheimer’s disease and related dementia. In: Ell PJ, Gambhir SS, eds. Nuclear Medicine in Clinical Diagnosis and Treatment 3rd ed. New York, NY: Churchill Livingstone, Inc.; 2004. In press.
  33. Devous MD Sr. Functional brain imaging in the dementias: role in early detection, differential diagnosis, and longitudinal studies. Eur J Nucl Med Mol Imaging. 2002;29:1685–1696.
    OpenUrlCrossRefPubMed
  34. ↵
    Mielke R, Pietrzyk U, Jacobs A, et al. HMPAO SPET and FDG PET in Alzheimer’s disease and vascular dementia: comparison of perfusion and metabolic pattern. Eur J Nucl Med. 1994;21:1052–1060.
    OpenUrlPubMed
  35. ↵
    DeCarli CS, Atack JR, Ball MJ, et al. Post-mortem regional neurofibrillary tangle densities but not senile plaque densities are related to regional cerebral metabolic rates for glucose during life in AD patients. Neurodegeneration. 1992;1:113–121.
  36. ↵
    Benson DF, Kuhl DE, Phelps ME, Cummings JL, Tsai SY. Positron emission computed tomography in the diagnosis of dementia. Trans Am Neurol Assoc 1981;106:68–71.
    OpenUrlPubMed
  37. Farkas T, Ferris SH, Wolf AP, et al. 18F-2-deoxy-2-fluoro-D-glucose as a tracer in the positron emission tomographic study of senile dementia. Am J Psychiatr. 1982;139:352–353.
    OpenUrlPubMed
  38. Foster NL, Chase TN, Fedio P, Patronas NJ, Brooks RA, Di Chiro G. AD: focal cortical changes shown by positron emission tomography. Neurology. 1983;33:961–965.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Frackowiak RS, Pozzilli C, Legg NJ, et al. Regional cerebral oxygen supply and utilization in dementia: a clinical and physiological study with oxygen-15 and positron tomography. Brain. 1981;104:753–778.
    OpenUrlFREE Full Text
  40. ↵
    Friedland RP, Jagust WJ. Positron and single photon emission tomography in the differential diagnosis of dementia. In: Duara R, ed. Positron Emission Tomography in Dementia. New York, NY: Wiley-Liss, Inc; 1990:161–177.
  41. Haxby JV. Resting state regional cerebral metabolism in dementia of the Alzheimer type. In: Duara R, ed. Positron Emission Tomography in Dementia. New York, NY: Wiley-Liss, Inc; 1990:93–116.
  42. Mazziotta JC, Frackowiak RSJ, Phelps ME. The use of positron emission tomography in the clinical assessment of dementia. Semin Nucl Med. 1992;22:233–246.
    OpenUrlCrossRefPubMed
  43. ↵
    Herholz K. FDG PET and differential diagnosis of dementia. Alzheimer Dis Assoc Disord. 1995;9:6–16.
  44. ↵
    Silverman DHS, Small GW, Phelps ME. Clinical value of neuroimaging in the diagnosis of dementia: sensitivity and specificity of regional cerebral metabolic and other parameters for early identification of AD. Clin Positron Imaging. 1999;2:119–130.
    OpenUrlCrossRefPubMed
  45. ↵
    Pietrini P, Alexander GE, Furey ML, Hampel H, Guazzelli M. The neurometabolic landscape of cognitive decline: in vivo studies with positron emission tomography in AD. Int J Psychophysiol. 2000;37:87–98.
    OpenUrlCrossRefPubMed
  46. ↵
    Mielke R, Schroder R, Fink GR, Kessler J, Herholz K, Heiss WD. Regional cerebral glucose metabolism and postmortem pathology in AD. Acta Neuropathol. 1996;91:174–179.
    OpenUrlCrossRefPubMed
  47. ↵
    Salmon E, Sadzot B, Maquet P, et al. Differential diagnosis of AD with PET. J Nucl Med. 1994;35:391–398.
    OpenUrlAbstract/FREE Full Text
  48. ↵
    Tedeschi E, Hasselback SG, Waldemar G, et al. Heterogeneous cerebral glucose metabolism in normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry. 1995;59:608–615.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    Hoffman JM, Welsh-Bohmer KA, Hanson M, et al. FDG PET imaging in patients with pathologically verified dementia. J Nucl Med. 2000;41:1920–1928.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Silverman DHS, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA. 2001;268:2120–2127.
    OpenUrl
  51. ↵
    Gambhir SS, Czernin J, Schwimmer J, Silverman DHS, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature [abstract]. J Nucl Med. 2001;42.(suppl):1S–93S.
    OpenUrl
  52. ↵
    Herholz K, Nordberg A, Salmon E, et al. Impairment of neocortical metabolism predicts progression in AD. Dement Geriatr Cogn Disord. 1999;10:494–504.
    OpenUrlCrossRefPubMed
  53. ↵
    Minoshima S, Giordani B, Berent S, Frey K, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early AD. Ann Neurol. 1997;42:85–94.
    OpenUrlCrossRefPubMed
  54. ↵
    Silverman DHS, Truong CT, Kim SK, et al. Prognostic value of regional cerebral metabolism in patients undergoing dementia evaluation: comparison to a quantifying parameter of subsequent cognitive performance and to prognostic assessment without PET. Mol Genet Metab. 2003;80:350–355.
    OpenUrlCrossRefPubMed
  55. ↵
    Small GW, Ercoli LM, Silverman DH, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for AD. Proc Natl Acad Sci USA. 2000;97:6037–6042.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    Truong C, Czernin J, Chen W, Phelps M, Silverman D. Improving specificity of PET for prognostic evaluation of dementia [abstract]. J Nucl Med. 2002;43.(suppl):62P.
    OpenUrl
  57. ↵
    Bench CJ, Friston KJ, Brown RG, Frackowiak RSJ, Dolan RJ. Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med. 1993;23:579–590.
    OpenUrlCrossRefPubMed
  58. ↵
    Silverman DHS, Geist CL, Van Herle K, et al. Abnormal regional brain metabolism in patients with hypothyroidism secondary to Hashimoto’s disease [abstract]. J Nucl Med. 2002;43.(suppl):254P.
    OpenUrl
  59. ↵
    Bauer M, Marseille DM, Geist CL, et al. Effects of thyroid hormone replacement therapy on regional brain metabolism [abstract]. J Nucl Med. 2002;43.(suppl):254P.
  60. ↵
    Bonte FJ, Devous MD. Single-photon emission computed tomographic imaging of the brain. In: Sandler MP, Coleman RE, Wackers FJTh, Patton JA, Gottschalk A, Hoffer PB, eds. Diagnostic Nuclear Medicine 4th ed. Baltimore, MD: Williams and Wilkins; 2004. In press.
  61. ↵
    Hoffman JM, Hanson MW, Welsh KA, et al. Interpretation variability of 18 FDG positron emission tomography studies in dementia. Invest Radiol. 1996;31:316–322.
    OpenUrlCrossRefPubMed
  62. Masterman DL, Mendez MF, Fairbanks LA, et al. Sensitivity specificity and positive predictive value of technetium 99m-HMPAO SPECT in discriminating AD from other dementias. J Geriatr Psychiatry Neurol. 1997;10:15–21.
  63. ↵
    Van Heertum RL, Tikofsky RS, Ruben AB. Dementia. In: Van Heertum RL, Tikofsky RS, eds. Functional Cerebral SPECT and PET Imaging. 3rd ed. New York, NY: Lippincott Williams and Wilkins; 2000:127–188.
  64. ↵
    Jagust W, Thisted R, Devous MD, et al. SPECT perfusion imaging in the diagnosis of AD: a clinical-pathologic study. Neurology. 2001;56:950–956.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Mielke R, Heiss WD. Positron emission tomography for diagnosis of AD and vascular dementia. J Neural Transm. 1998;53.(suppl):237–250.
    OpenUrl
  66. ↵
    Messa C, Perani D, Lucignani G, et al. High-resolution technetium-99m-HMPAO SPECT in patients with probable Alzheimer’s disease: comparison with fluorine-18-FDG PET. J Nucl Med. 1994;35:210–216.
    OpenUrlAbstract/FREE Full Text
  67. ↵
    Herholz K, Schopphoff H, Schmidt M, et al. Direct comparison of spatially normalized PET and SPECT scans in Alzheimer’s disease. J Nucl Med. 2002;43:21–26.
    OpenUrlAbstract/FREE Full Text
  68. ↵
    Galasko D, Hansen LA, Katzman R, et al. Clinical-neuropathological correlations in AD and related dementias. Arch Neurol. 1994;51:888–895.
    OpenUrlCrossRefPubMed
  69. ↵
    Silverman DHS, Cummings JL, Small GW, et al. Assessment of the added clinical benefit of incorporating FDG-PET into the clinical evaluation of patients with cognitive impairment. Mol Imaging Biol. 2002;4:283–293.
    OpenUrlCrossRefPubMed
  70. ↵
    Mittelman MS, Ferris SH, Shulman E, Steinberg G, Leving B. A family intervention to delay nursing home placement of patients with Alzheimer’s disease: a randomized, controlled trial. JAMA. 1996;276:1725–1731.
    OpenUrlCrossRefPubMed
  71. ↵
    Rinne JO, Kaasinen V, Jarvenpaa T, et al. Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer’s disease. J Neurol. 2003;74:113–115.
    OpenUrl
  72. ↵
    Kopcho LM, Ma J, Marcinkeviciene J, et al. Comparative studies of active site-ligand interactions among various recombinant constructs of human beta-amyloid precursor protein cleaving enzyme. Arch Biochem Biophys. 2003;410:307–316.
    OpenUrlCrossRefPubMed
  73. ↵
    Vander Borght T, Minoshima S, Giordani B, et al. Cerebral metabolic differences in Parkinson’s and ADs matched for dementia severity. J Nucl Med. 1997;38:787–802.
    OpenUrl
  74. ↵
    Imamura T, Ishii K, Sasaki M, et al. Regional cerebral glucose metabolism in dementia with Lewy bodies and AD: a comparative study using positron emission tomography. Neurosci Lett. 1997;235:49–52.
    OpenUrlCrossRefPubMed
  75. ↵
    Ishii K, Sakmoto S, Sasaki M, et al. Cerebral glucose metabolism in patients with frontotemporal dementia. J Nucl Med. 1998;39:1875–1878.
    OpenUrlAbstract/FREE Full Text
  76. ↵
    Ishii K, Sasaki M, Yamaji S, Sakamoto S, Kitagaki H, Mori E. Paradoxical hippocampus perfusion in mild-to-moderate AD. J Nucl Med. 1998;39:293–298.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    De Santi S, de Leon MJ, Rusinek H, et al. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging. 2001;22:529–539.
    OpenUrlCrossRefPubMed
  78. ↵
    Jagust WJ, Eberling JL, Wu CC, et al. Brain function and cognition in a community sample of elderly Latinos. Neurology. 2002;59:378–383.
    OpenUrlAbstract/FREE Full Text
  79. ↵
    De Leon MJ, Convit A, Wolf OT, et al. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/positron-emission tomography (FDG/PET). Proc Natl Acad Sci USA. 2001;98:10966–10971.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    Chetelat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron JC. Mild cognitive impairment: can FDG-PET predict who is to rapidly convert to Alzheimer’s disease? Neurology. 2003;60:1374–1377.
    OpenUrlAbstract/FREE Full Text
  81. ↵
    Drzezga A, Lautenschlager N, Siebner H, et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging. 2003;30:1104–1113.
    OpenUrlCrossRefPubMed
  82. ↵
    Arnaiz E, Jelic V, Almkvist O, et al. Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment. Neuroreport. 2001;12:851–855.
    OpenUrlCrossRefPubMed
  83. ↵
    Mayeux R, Saunders AM, Shea S, et al. Utility of the apolipoprotein E genotype in the diagnosis of AD. AD Centers Consortium on Apolipoprotein E and AD. N Engl J Med. 1998;338:506–511.
    OpenUrlCrossRefPubMed
  84. ↵
    Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58:397–405.
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Bookmark this article

Jump to section