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The role of positron emission tomography imaging of β-amyloid in patients with Alzheimer's disease

Xiong, Kun-Lina; Yang, Qing-Wub; Gong, Shui-Gena; Zhang, Wei-Guoa

Nuclear Medicine Communications: January 2010 - Volume 31 - Issue 1 - pp 4-11
doi: 10.1097/MNM.0b013e32833019f3
Review Article

One of the hallmark pathologies of Alzheimer's disease (AD) is amyloid plaque deposition in the brain. Although the advent of new therapeutic strategies aimed at reducing β-amyloid burden in the brain is to potentially delay cognitive loss, improved methods for amyloid visualization have become more imperative. Studies so far have shown that positron emission tomography (PET) has produced the greatest strides toward accomplishing this ambitious goal. Several PET amyloid imaging ligands have recently been developed and tested in AD patients. High amyloid content can be detected in vivo by PET in prodromal AD preceding the impairment of functional activity. Hopefully, amyloid imaging may help in the early detection of the disease and can be used for evaluating new drug therapies in AD. This study provides an overview of recent advances in the development of amyloid imaging agents and includes a summary of the clinical significance of amyloid imaging.

Departments of aRadiology

bNeurology, The Third Affiliated Hospital, The Third Military Medical University, China

Correspondence to Dr Wei-Guo Zhang, MD, Department of Radiology, The Third Affiliated Hospital, The Third Military Medical University, No. 10 Changjiang Branch Road, Chongqing 400042, China

Tel: +86 23 68757621; e-mail:

Received 3 April 2009 Revised 25 June 2009 Accepted 25 June 2009

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Alzheimer's disease (AD) is the most common cause of progressive cognitive impairment among the expanding elderly population [1]. It is expected that the number of AD patients worldwide will increase from 26.6 million in 2006 to 106.8 million by 2050 [2]. AD is the fourth leading cause of death in industrialized societies, exceeded only by heart disease, cancer, and stroke [2]. The cost of dementia for a population of 29.3 million worldwide was recently estimated to be 315 billion US dollars [3]. These numbers highlight the need for early diagnosis and effective therapeutic intervention for AD.

The standard diagnostic workup for AD includes clinical, psychiatric, and neurological examination; psychometric testing; and anatomic imaging, such as computed tomography and magnetic resonance imaging (MRI) [4]. This approach is sensitive and specific enough for the diagnosis of AD only at the middle or late stages of the disease. However, diagnosis of preclinical stages of AD, even for the mild cognitive impairment (MCI) symptomatic characterization, is not always accurate [4]. There is currently a lack of sensitive and specific diagnostic criteria for early AD. In the last decade, neuroimaging has been increasingly used to complement clinical assessments in the early detection of AD. Metabolic positron emission tomography (PET) and structural MRI are the most clinically used and promising modalities to detect brain abnormalities in individuals who might be at risk for AD but who have not yet developed symptoms [5].

AD is characterized by the presence and abundance of amyloid plaques and neurofibrillary tangles (NFTs) in brain tissue. Amyloid plaques are predominantly composed of insoluble β-amyloid (Aβ) peptides, mostly Aβ1–42 and Aβ1−40, with Aβ1−42 being the most prevalent component [6]. NFTs are composed mainly of hyperphosphorylated forms of the microtubule-associated protein tau [7]. To date, the pathology of AD remains unknown. Growing evidence indicates that cerebral Aβ accumulation is the primary influence in AD and that the rest of the disease process, including formation of NFTs containing tau protein, results from an imbalance between Aβ production and Aβ clearance [8–11].

As Aβ is a known component of AD pathogenesis, and given that several pharmacological agents aimed at reducing Aβ levels in the brain are being developed and tested [12], many efforts have focused on developing radiotracers for PET that allow Aβ imaging in vivo [13–16], and some of these have entered into preliminary clinical studies in recent years [16,17]. Therefore, this review will mainly summarize current efforts made in amyloid imaging with PET and discuss their potential importance in clarifying the clinical relevance of amyloid plaque to AD.

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Functional magnetic resonance imaging in Alzheimer's disease

Functional MRI (fMRI) is used to measure signal intensities that are associated with relative cerebral blood flow during memory or other cognitive tasks. There is evidence that early changes in activation during memory tasks can precede and predict the occurrence of AD [18]. fMRI studies of patients with AD show lowered brain activity in parietal and hippocampal regions and relatively higher activity in primary cortices unaffected by the disease [19]. The application of fMRI also involves the measurement of the extent to which different areas of the brain are functionally connected. During mental rest, patients with AD show less coordinated activity in a brain network (e.g. posterior cingulate, hippocampus, and inferior parietal lobes) [20]. However, patients with dementia are usually too impaired to perform such memory tasks. It should be noted that the utility of fMRI relies on the validity of linking clinical response to blood flow changes. It is entirely conceivable that a significant cognitive improvement could occur without any concomitant change in the regional blood flow response to cognitive activity. Therefore, the realization of the potential of fMRI technology in the content of clinical trials of AD will depend on its technical maturation and continuing validation of its association with clinical symptoms.

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[18F]FDG-PET in Alzheimer's disease

PET has long been used to assess various forms of dementia, with AD being the most common subtype [13,21,22]. A considerable literature now exists with regard to the role of [18F]fluorodeoxyglucose (FDG)-PET in the early diagnosis of AD and the progressive changes in PET metabolism with disease progression [23,24]. Such studies have shown characteristic cortical brain alterations in AD that begin in the posterior cingulate and parietal regions, and then spread to the temporal and prefrontal cortices [23]. Such images can differentiate patients with AD from those with other dementias and controls [23,25]. Regional cortical hypometabolism correlates with greater cognitive losses. Diagnostic accuracy for AD seems better when [18F]FDG-PET is added to the standard clinical assessment of dementia, providing increased sensitivity and specificity of diagnosis [26]. Automatic diagnostic expert systems using FDG-PET are currently being developed [24]. Lower scanner costs and greater availability of PET tracers is expected to lead to wider use of PET for dementia diagnosis.

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Positron emission tomography imaging of β-amyloid in Alzheimer's disease

Perhaps the search for newer radiotracers that can be used in the evaluation of patients with AD is interesting in current molecular imaging research. During the past few years, several groups have set out to develop PET radioligands that bind to amyloid plaques and NFTs in an effort to visualize and localize plaques and tangles in living patients [27]. The desired properties of imaging agents for amyloid plaques are similar to the characteristics required for any brain-penetrated imaging agent [28]. These properties include high affinity and selectivity for the target Aβ structure, moderate lipophilicity (log P in the range of 1–3.5 is preferred) for good brain entry and rapid clearance from the normal brain [29], low nonspecific binding and fast pharmacokinetics, limited molecular mass (<500) for brain entry [30], and functional groups in the molecule for introduction of positron emitting radionuclides, such as 11C (t1/2 = 20 min) or 18F (t1/2 = 109 min).

To date, five novel amyloid imaging tracers, [18F]FDDNP [31], [11C] Pittsburgh Compound B (PIB) as N-methyl [11C] 2-(4′-methylaminophenyl)-6-hydroxy-benzothiasole [32], [11C]SB-13 as 4-N-methylamino-4′-hydroxystilbene [33], [11C]BF-227 as 2-(2-[-dimethylaminothizol-5-yl] ethenyl)-6-(2-[fluoro] benzoxazole) [34], and [18F] BAY94-9172 as trans-4-(N-methylamino)-4A˚L-{2-[2-(2-[18F]fluoro-ethoxy)-ethoxy]-ethoxy}-stilbene [35] have been tested in PET studies in clinical patients and controls (Fig. 1).

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In 2002, [18F]FDDNP-PET was the first PET study in patients with AD and healthy humans [31,36]. FDDNP is a fluorinated derivative of a lipophilic, viscosity and solvent-sensitive compound [27]. FDDNP intensely labels the dense core and diffuse amyloid plaques, and faintly labels NFTs [37], which complicates the interpretation of a specific signal in vivo. [18F]FDDNP was initially tested in nine AD patients and later in 25 additional AD patients [25,31]. Administration of [18F]FDDNP showed good brain penetration and specific retention in the hippocampus, amygdala, and entorhinal regions in AD patients [25,31,36]. Moreover, the greater degree of [18F]FDDNP retention in these brain regions correlated well with lower memory performance scores [25,38]. The researchers found significantly higher binding in patients with AD compared with those with MCI or controls, and higher binding in MCI patients compared with controls, indicating the potential use of this compound in the early diagnosis of AD [25,38]. More recent research further showed that [18F]FDDNP scanning can discriminate between individuals with MCI, those with AD, and those with no cognitive impairment [39]. Consistent with the [18F]FDG-PET findings, brain regions with low glucose metabolism were generally matched with those that showed higher retention of [18F]FDDNP [31].

However, there is currently limited experience with this PET radioligand worldwide, and it has been sparingly used because of a relatively high background signal [40] and a relatively low specific binding signal [25]. Finally, [18F]FDDNP has been shown to compete for the same binding site on amyloid fibrils as the nonsteroidal naproxen and ibuprofen, which may significantly reduce or eliminate the signal from this ligand in individuals taking these medications [41]. Therefore, [18F]FDDNP could be useful for assessing the neuropathological progression of AD rather than specific evaluation of Aβ deposits in the brain.

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[11C]PIB and [18F]PIB

[11C]PIB, a promising amyloid ligand, is the most thoroughly investigated PET radioligand in the study of human Aβ plaques. PIB is a thioflavin-T (ThT) or benzothiazole derivative. PIB has a favorable combination of a high affinity to Aβ (Ki = 4.3 nmol/l to Aβ1–40 fibrils), and a moderate log P value of 1.2, which allows for high initial uptake combined with fast clearance from the normal brain [42]. This is reflected in the low nonspecific binding and rapid clearance of PIB in the mouse brain, as defined by the relatively high ratio of [11C]PIB uptake at 2 versus 30 min [43].

The first studies of [11C]PIB in humans was conducted in Sweden in collaboration with the University of Pittsburgh in 2002. There was a significantly higher retention of PIB in 16 AD patients, particularly in the frontal, temporal, parietal, and occipital cortices and the striatum, when compared with nine healthy controls [32]. The absolute amount of [11C]PIB retained was most prominent in the frontal cortex of AD patients (194% of control), and significantly higher in the parietal cortex (171%), temporal cortex (152%), occipital cortex (154%), and striatum (176%) [32]. The [11C]PIB retention matches the distribution of Aβ deposits in postmortem studies of human AD brains [44], and correlates inversely with cerebral glucose metabolism determined with [18F]FDG, especially in the area of the parietal cortex [45]. In addition, the retention of PIB was low and similar in the pons and cerebellum of AD and control groups [32]. This first pioneering observation with PIB has been consistently confirmed by several research groups [45–52].

[11C]PIB-PET studies have indicated that [11C]PIB has the potential to allow for the visualization of the degree and distribution of Aβ deposits in the cortical regions of the AD brain. A typical difference in [11C]PIB retention among AD, MCI, and control is illustrated in Fig. 2 [53]. Moreover, a more recent [11C]PIB-PET imaging study in age-matched individuals with AD, MCI, or with no cognitive dysfunction has been conducted by Grimmer et al. [54]. A difference in PIB binding was observed between AD patients and controls in the frontal, temporal, parietal, and posterior cingulate cortices, whereas patients with MCI resembled either controls or patients with AD [54]. However, other studies in patients with MCI consistently showed a retention pattern of [11C]PIB, which is comparable with patients with AD in approximately half of the MCI patients, whereas the other half showed a pattern more similar to healthy controls [45,49]. Although the prognostic value of these findings is not completely clear, these results show that MCI patients who later develop AD show significantly higher PIB retention compared with MCI patients who do not develop AD [49]. Although the initial prospect of [11C]PIB as an amyloid plaque imaging agent is promising, large-scale studies are necessary to validate the utility of this PET tracer in discriminating AD patients from controls, and, most significantly, from patients diagnosed with MCI.

More recently, researchers from the University of Pennsylvania compared the amyloid imaging agents, [11C]PIB and [18F]3′-F-PIB, in patients with AD and healthy controls [55]. The 18F-labeled compound showed uptake and retention characteristics similar to those of [11C]PIB in cortical brain regions. Another similar study corroborated this finding and concluded that the 18F-labeled PET ligand might have a wide application because of its longer half-life and ease of distribution compared with [11C]PIB [56]. Commercial development of [18F]PIB is in progress, which should make this amyloid imaging compound even more accessible in coming years.

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[11C]SB-13 is extensively studied among the proposed amyloid tracers derived from styrylbenzene [57,58]. It is a lead amyloid radioligand with high affinity for Aβ (Ki = 6.0 nmol/l on Aβ1–40 fibrils), moderate lipophilicity (log P = 2.4), a high initial brain uptake, and relatively rapid washout from the normal rat brain after an intravenous injection [57,59].

A human PET study of [11C]SB-13 was conducted to evaluate its potential as an amyloid imaging agent in 11 AD patients and five healthy controls [33]. In AD patients, both tracers showed significantly higher retention in cortical regions compared with healthy controls, and the relative cortical uptakes were higher for [11C]SB-13 than for [11C]PIB [33]. In a comparative evaluation between AD patients and controls, the binding potentials derived from SB-13 imaging were highly discriminated in the frontal and occipital cortices and striatum, whereas the potentials from PIB imaging showed higher discriminations not only in those cortices, but also in the temporal cortex. In addition, [11C]SB-13 had a higher uptake in healthy controls [33]. It should be noted that the sample size in this study was relatively small. Overall, although slight differences between [11C]SB-13 and [11C]PIB were found, [11C]SB-13 seems to be an effective PET tracer for imaging Aβ deposits in the AD brain, with performance similar to that of [11C]PIB.

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Recently, amyloid imaging with a stilbene derivative, [11C]BF-227, has been evaluated in AD patients and healthy controls [34]. In controls, [11C]BF-227 showed rapid brain uptake and clearance in cortical regions. However, AD patients showed slower than normal clearances of [11C]BF-227 in the frontal, temporal, and parietal cortices. In contrast to the cortical regions, the brain uptake and clearance in the cerebellum was nearly identical between controls and AD patients. Relative to [11C]PIB, [11C]BF-227 was observed to bind more strongly to temporo–parietal–occipital regions than to the frontal cortex and striatum [34]. This indicates that [11C]BF-227 might preferentially bind to more dense amyloid, but further comparative studies are needed between the two PET amyloid imaging compounds to fully understand this concept. These results also suggest that [11C]BF-227 is a potent PET probe for the in-vivo detection of amyloid deposits in AD patients.

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[18F]BAY94-9172 is also a stilbene derivative that has recently been evaluated in preliminary clinical studies [35]. A PET study of [18F]BAY94-9172 was conducted in 15 patients with mild AD, 15 healthy elderly controls, and five individuals with frontal temporal lobar degeneration (FTLD). [18F]BAY94-9172 binding was quantified by use of the standardized uptake value ratio, which was calculated for the neocortex using the cerebellum as reference region. [18F]BAY94-9172 binding matched the reported postmortem distribution of the Aβ plaques [35]. All AD patients showed widespread neocortical binding, which was greater in the precuneus/posterior cingulate and frontal cortex than in the lateral temporal and parietal cortex. Healthy controls and FTLD patients showed only white matter binding, although three controls and one FTLD patient had mild uptake in frontal and precuneus cortex. In addition, [18F]BAY94-9172 showed a binding pattern in AD brains similar to that of PIB [35]. A more recent study of the radiation dosimetry of [11C]PIB and [18F]BAY94-9172 showed similar dosimetry in vivo [60]. These results suggest that [18F]BAY94-9172 might be suitable for clinical application for amyloid imaging.

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Amyloid imaging for early detection of Alzheimer's disease

A considerable literature now exists with regard to the role of FDG-PET in the early diagnosis of AD [23,24], which underlies the potential for PET imaging to supply additional information not obtainable from clinical evaluation. The development of a reliable neuroimaging method of assessing Aβ burden in vivo would permit early diagnosis at presymptomatic stages of AD [53].

PET amyloid imaging studies in humans have shown a robust difference between the retention pattern in AD patients and healthy controls, with AD cases showing significantly higher retention of [11C]PIB in neocortical areas of the brain affected by Aβ deposition [32,33,49,61]. Multimodality studies in early AD have also shown Aβ deposits in posterior cortical regions that are associated with memory retrieval in young adults [61].

Although Aβ plaques are one of the characteristic features of AD confirmed by postmortem evaluation, Aβ deposits in the brain are not unique to clinically apparent AD, and these deposits have been found with normal aging [62]. Aβ deposition is believed to begin in normal elderly individuals, who may subsequently develop signs of MCI and then may finally develop AD (Fig. 2). Recent PET studies using [11C]PIB in elderly normal controls support the existence of a preclinical AD stage in which Aβ plaques are found predominantly in the prefrontal cortex and posterior cingulate/precuneus areas by showing the presence of significant radioligand retention, approaching levels observed in AD patients, in approximately 10% of the elderly controls [48]. The demonstration of [11C]PIB binding in a proportion of healthy controls support postmortem observations that Aβ aggregation predominantly occurs before the onset of dementia [48,49].

Furthermore, ongoing longitudinal follow-up studies will permit full elucidation of the significance of [11C]PIB binding in the elderly controls and MCI patients. A recent PET amyloid imaging study has shown a strong relationship between impaired memory performance and Aβ burden in MCI, but not in the AD group [63]. A preliminary report has also shown that seven of 21 MCI patients developed AD within 2–16 months after their [11C]PIB-PET scan [64]. MCI patients who later developed AD showed a higher [11C]PIB retention than patients who did not develop AD, and their [11C]PIB retention was highly correlated with cerebrospinal fluid (CSF) biomarkers and memory impairment [64]. In contrast, Rowe et al. [49] have observed very little change in Aβ burden in 28 healthy control, 11 MCI, and 18 AD patients in follow-up [11C]PIB PET studies approximately 21 months apart, with an overall increase in Aβ burden of 6.2% in the AD group, which is slightly below the reported test–retest reproducibility for [11C]PIB PET studies [65,66]. Both the healthy control and MCI groups showed almost no change in Aβ burden (0.9 and 2.4%, respectively). In contrast, 10 of 18 MCI patients who later developed AD were [11C]PIB-positive on their baseline assessment [49]. These findings, in addition to the evidence of Aβ deposition in a high percentage of MCI and asymptomatic healthy controls, suggest that Aβ is an early and necessary cause for cognitive decline in AD.

In summary, amyloid imaging seems to be the ideal approach to evaluate MCI patients. Although Aβ burden as assessed by PET does not correlate with measures of cognitive decline in AD, it does correlate with memory impairment and rate of memory decline in MCI and healthy elderly individuals. Approximately, 30% of asymptomatic controls present cortical [11C]PIB retention. These observations also suggest that Aβ deposition is not part of normal aging, supporting the hypothesis that Aβ deposition occurs well before the onset of symptoms and is likely to represent preclinical AD.

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Amyloid imaging for evaluation of antiamyloid therapy

Several therapeutic strategies for preventing or diminishing insoluble Aβ accumulation, such as secretase inhibitors or modulators, Aβ vaccines, tau kinase inhibitors, cholesterol-lowering statins, and anti-inflammatory drugs, are being evaluated as interventions for delaying onset or slowing the progression of AD [67]. Some of these approaches might provide disease-modifying effects and slow the progression of neurodegeneration. Although neuroimaging for brain Aβ might measure the biological effects of the intervention, a clinical trial design that would assess the progression of AD would be necessary to prove disease-modifying effects [68]. Combining neuroimaging with other biological markers might improve diagnostic accuracy, reduce the number of individuals needed for a clinical trial of a new treatment, and identify genetically defined subgroups of patients who are most likely to respond to certain treatments [69]. The currently available amyloid imaging ligands will be valuable for monitoring any reduction in Aβ plaques.

To date, several immunization therapy approaches are being explored in which amyloid imaging is the outcome measure of reduction in plaque load in the brain [70,71]. The first immunotherapeutic approach in clinical trials involved active immunization with Aβ1–42 itself [70]. Unfortunately, this AN-1792 trial was suspended because of a 6% incidence of meningoencephalitis [70]. The anticipated effects of AN-1792 on Aβ load were displayed with [3H]PIB-binding assay in postmortem frontal cortex tissue. The frontal cortex from the AN-1792-treated AD patient shows values similar to those of controls, indicating the absence of Aβ plaque pathology. The question also arises as to whether this AN-1792-treated patient had an Aβ plaque pathology in the frontal cortex before treatment. Studies using Aβ imaging agents, such as [11C]PIB, at baseline and after antiamyloid treatment, will help in answering this question. Currently, [11C]PIB is being used in antiamyloid drug development trials in clinically diagnosed mild-to-moderate AD patients to quantitatively assess changes in amyloid plaque densities throughout the brain over the course of the experimental treatments. Accurate pretreatment baseline measures of [11C]PIB binding in these patients will determine a reference point against which to judge the effectiveness of the treatments in clearing amyloid plaque burden, as well as confirm the clinical diagnosis of AD.

More recently, the long-term effect of phenserine, a cholinesterase inhibitor [72], was evaluated in mild AD patients using [11C]PIB-PET, and a reciprocal change was observed between reduction in [11C]PIB retention in the brain and an increased level of CSF Aβ1–40 [73]. Cerebral glucose metabolism was also increased and correlated positively with cognitive function and CSF Aβ1−40 levels [73]. This is the first study to report the use of PIB in the evaluation of drug effects, and thus supports the assumption that amyloid imaging will be valuable for the assessment of new drug development in AD. However, it should be noted that only patients with detectable Aβ loads will show decreases in [11C]PIB binding with anti-Aβ therapies. Elderly controls and MCI patients with no evidence of Aβ deposition are unlikely to show changes in [11C]PIB binding with antiamyloid therapy. Importantly, [11C]PIB and related compounds should be able to detect decreases in insoluble Aβ load approximately two-fold greater than the test–retest variability of the imaging method [74]. For [11C]PIB, the test–retest variability depends on the data analysis method and the region of interest [74], but the difference is in the range of 5–10%. Thus, 10–20% decreases in the Aβ load should prove to be detectable with [11C]PIB.

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Imaging neurofibrillary tangles

Significant progress has been made in imaging amyloid plaques in the brain of laboratory animals and humans. However, progress in the development of specific radioligands to image NFTs in the living brain has been much less rapid [30]. Congo Red (CR) is an amyloid-staining agent widely used in histological studies of postmortem AD brain tissue sections. CR also stains NFTs [75]. However, CR is a negatively charged sulfonate at physiological conditions and is too hydrophilic to penetrate the blood–brain barrier. In addition to CR, thioflavin-S and ThT are commonly used for in-vitro staining of amyloid plaques and NFTs. Nanomolar concentrations of [3H]BTA-1, a ThT derivative, did not appear to bind to NFTs, but micromolar concentrations did, indicating that the affinity of [3H]BTA-1 for NFTs was several orders of magnitude lower than that of Aβ [76]. In addition, FDDNP intensely labels the dense core and diffuse amyloid plaques, but faintly labels NFTs [37]. Therefore, so far there is no specific tracers to identify NFTs in vivo, and imaging NFTs remains to be fully characterized and demonstrated.

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Conclusions and future prospects

In current clinical practice, MRI is routinely used and [18F]FDG-PET is sometimes used to assist in the diagnosis of AD. With the recent advances in neuroimaging technology, additional methods are emerging as potentially useful. The initial PET studies using [11C]PIB, [18F]FDDNP, and [11C]SB-13 in AD patients are encouraging because they broadly show retention of the probes in areas of the brain associated with Aβ deposition. Aβ imaging can provide the clinician with better prediction of conversion from MCI to AD than the clinical criteria. Aβ may also assist in the development of antiamyloid therapy. Imaging NFTs, separately or in concert with Aβ plaques, is not as far advanced as imaging Aβ plaques and remains to be fully explored.

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Alzheimer's disease; amyloid; diagnosis; neuroimaging; positron emission tomography; therapy

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