There are many unknowns that could impact the diagnostic utility of amyloid PET. First, the sensitivity and specificity compared with pathology are not yet well defined. Technical and patient factors that could lead to false positives and false negatives are not clear. PIB binds to both diffuse and neuritic plaques [6
] (the latter being more common in normal aging), and the relative contribution of each to the in vivo
signal has not been determined. It is not yet clear whether amyloid PET should be interpreted as a dichotomous test (that is, positive versus negative) or whether the degree and spatial distribution of binding offer additional diagnostic information. Studies examining inter-rater and intra-rater reliability of visual interpretations are few, and the optimal quantitative threshold for defining a positive scan has not yet been defined [87
]. Also not yet established is whether the threshold for PIB-positivity should be adjusted based on demographic factors such as age (as is done when scoring plaques at autopsy) [43
] or genetic variables such as the ApoE ε4 genotype. Significantly, the relationship between amyloid and dementia is weaker in older versus younger individuals [88
]. The positive predictive value of a positive amyloid scan in determining the cause of dementia will therefore be lower in older individuals. In general, amyloid PET will be more useful in ruling out (given the high sensitivity for pathology) than in ruling in AD as the cause of dementia, since the detection of amyloid may be incidental or secondary to a primary, non-Aβ pathology in some cases (for example, Case 3 above).
The ideal combination of biomarkers in the evaluation of dementia will probably depend on the specific clinical scenario. In general, the approach introduced in the new AD diagnostic guidelines (one marker specific for Aβ, another specific for neurodegeneration to establish AD as the probable pathophysiology) has face validity [56
]. However, one can imagine that an amyloid scan will add more diagnostic value to a structural image in a 60 year old with an atypical MCI syndrome and hippocampal atrophy (which may or may not be due to AD pathology) than in an 80 year old with clinically classical AD dementia and a clear temporo-parietal cortical atrophy pattern. A number of studies have evaluated the utility of combining amyloid scans with MRI [25
] or FDG [89
], but these analyses have largely been limited to the MCI/AD continuum. Also, the relative diagnostic strengths of CSF versus amyloid imaging as molecular markers have yet to be determined. While amyloid tracer binding correlates highly with CSF Aβ1-42
levels across the AD continuum [91
], how CSF AD biomarkers and amyloid imaging compare in differentiating AD from other causes of dementia remains to be seen. Initial studies suggest that CSF Aβ1-42
may be more sensitive than PIB to early amyloid pathology [20
], rendering CSF potentially more sensitive for early detection but less specific in determining the cause of dementia. The lack of specificity may be overcome, however, by applying a ratio of Tau/Aβ1-42
]. Further head-to-head studies of amyloid PET and CSF are needed to clarify these points. For current practice, we recommend structural neuroimaging as the standard of care for ruling out nondegenerative causes of cognitive decline [94
]. A molecular marker (either amyloid PET or CSF) may have added value in particular scenarios, as discussed below. In some clinical scenarios, a nonamyloid molecular tracer may be preferred (for example, dopamine imaging for differentiating AD and DLB) [95
Ultimately, to be widely adopted a diagnostic test needs to have a significant impact on patient management and outcomes, and to be cost-effective. Few studies have examined these points with regard to amyloid imaging. In our clinic, PIB results have had implications for treatment, mainly affecting decisions about whether to initiate or discontinue AD symptomatic medications (see case histories). In practice, these medications are probably prescribed to a large number of patients with non-AD dementia, whereas certain populations that may benefit are currently not treated (for example, MCI due to AD) based on negative clinical trials that may have been confounded by biological heterogeneity [96
]. Such decisions would be more rational if amyloid PET was applied in the right circumstances, and this could result in cost saving. The more immediate impact of amyloid imaging will be in improving clinical trial design by enrolling patients based on biological, rather than clinical, phenotype. This is a necessary first step for the development and testing of disease-specific therapies. Initial studies have found that requiring a positive molecular biomarker for inclusion will render AD clinical trials more efficient and less costly, especially in early disease stages [97
]. In fact, a positive amyloid scan may be the primary inclusion criterion for a study focused on AD prevention.
Recommendations for potential clinical applications of amyloid PET are provided in Table . These applications are based on our analysis of the data and our institutional experience, and represent an early attempt to guide clinicians in how to apply amyloid PET to their practice. The recommendations were formulated using the following principles: amyloid PET cannot be interpreted in the absence of clinical context (as is the case with any diagnostic test); amyloid PET will be most useful in differentiating Aβ from non-Aβ causes of dementia in scenarios in which this distinction is clinically challenging - these scenarios might include patients with mild symptoms (for example, MCI), cases presenting with pathologically heterogeneous clinical syndromes (for example, PPA, CBS), patients with early age-of-onset dementia, or cases with symptoms that could be explained by either Aβ processes or nondegenerative causes (for example, NPH, intracranial microhemorrhages); and, finally, some very important applications of amyloid PET should be restricted to research studies (for example, scanning asymptomatic or minimally symptomatic patients).
Clinical and research utility of amyloid imaging