Positron emission tomography (PET) with amyloid ligands
has revolutionized neuroimaging of aging and dementia
in the past decade by enabling the detection and quanti-
fi cation of amyloid plaques, a core pathologic feature of
Alzheimer’s disease (AD) . Th e fi rst specifi c tracer for
amyloid-beta (Aβ) applied in human studies was
carbon-11 (11C)-labeled Pittsburgh Compound B (PIB).
PIB is an analogue of thiofl avin-T that, at PET tracer
concentrations, binds to fi brillar Aβ deposits with high
sensitivity and specifi city [2,3]. PIB binds to both extra-
cellular amyloid plaques (composed primarily of the
Aβ 1–42 peptide (Aβ1–42)) and vascular amyloid deposits
(consisting mainly of Aβ 1–40 peptides) . At PET
tracer concentrations, PIB does not bind to non-Aβ
inclusions such as neurofi brillary tangles or Lewy bodies
[5,6] or to brain homogenates from patients with non-Aβ
PIB-PET has rapidly become an integral part of research
studies on cognitive aging and the evolution of AD. Th e
20-minute half-life of 11C, however, limits its use to
research centers equipped with a cyclotron, and precludes
widespread clinical application. More recently, a second
generation of amyloid tracers labeled with fl uorine-18
(18F, 110-minute half-life) has been developed, making it
feasible to produce and distribute amyloid tracers for
clinical use . Th ree 18F amyloid imaging agents are in
advanced stages of development: fl utemetamol, a
3’-fl uoro analog of PIB; fl orbetapir, a styrylpyridine
derivative; and fl orbetaben, a derivative of stilbene. Th ese
tracers have performed comparably with PIB in clinical
populations, although nonspecifi c white matter binding
appears to be higher [9-11]. PIB, fl orbetapir and fl ute-
metamol have been validated prospectively compared
with the autopsy diagnosis of AD, and in vivo tracer
binding of all three shows high correlation with post-
mortem measures of fi brillar Aβ [3,9,12].
In addition to research applications, amyloid imaging
has great potential as a diagnostic tool because it directly
detects a core feature of the molecular pathology of AD.
Th is stands in contrast to currently available diagnostic
imaging techniques in dementia, which detect the down-
stream eff ects of pathology on the brain, such as synaptic
dysfunction (fl uorodeoxyglucose (FDG)-PET) and neuronal
In the past decade, positron emission tomography
(PET) with carbon-11-labeled Pittsburgh Compound
B (PIB) has revolutionized the neuroimaging of
aging and dementia by enabling in vivo detection
of amyloid plaques, a core pathologic feature of
Alzheimer’s disease (AD). Studies suggest that PIB-
PET is sensitive for AD pathology, can distinguish AD
from non-AD dementia (for example, frontotemporal
lobar degeneration), and can help determine whether
mild cognitive impairment is due to AD. Although
the short half-life of the carbon-11 radiolabel has
thus far limited the use of PIB to research, a second
generation of tracers labeled with fl uorine-18 has
made it possible for amyloid PET to enter the clinical
era. In the present review, we summarize the literature
on amyloid imaging in a range of neurodegenerative
conditions. We focus on potential clinical applications
of amyloid PET and its role in the diff erential diagnosis
of dementia. We suggest that amyloid imaging will be
particularly useful in the evaluation of mildly aff ected,
clinically atypical or early age-at-onset patients, and
illustrate this with case vignettes from our practice. We
emphasize that amyloid imaging should supplement
(not replace) a detailed clinical evaluation. We caution
against screening asymptomatic individuals, and discuss
the limited positive predictive value in older populations.
Finally, we review limitations and unresolved questions
related to this exciting new technique.
© 2010 BioMed Central Ltd
Amyloid imaging in the diff erential diagnosis
of dementia: review and potential clinical
Robert Laforce Jr* and Gil D Rabinovici
*Corresponding author: firstname.lastname@example.org
Memory and Aging Center, Department of Neurology, University of California San
Francisco, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94143, USA
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
© 2011 BioMed Central Ltd
loss (magnetic resonance imaging (MRI)/computed
tomography) – events that are thought to occur late in
the disease cascade . Indeed, the clinical utility of
amyloid tracers is currently being debated by regulatory
In the present review, we focus on potential clinical
applications of amyloid imaging. We summarize the litera-
ture on amyloid imaging in a range of neurodegenerative
conditions, most of which consists of PIB studies. Data
from 18F tracer studies are presented when available. We
restrict our review to tracers that specifi cally bind to Aβ,
and therefore do not discuss fl uoro-dicyano-dimethyl-
amino-naphthalenyl propene, a tracer that binds to a
number of pathologic inclusions that have an amyloid
conformation . We comment on the potential clinical
utility of amyloid PET in a variety of clinical scenarios,
and provide examples from patients enrolled in a study of
amyloid imaging at our institution. Finally, we summarize
our recommendations for clinical use of amyloid imaging,
and discuss limitations and unresolved questions related
to this exciting new technique.
Amyloid PET in various clinical populations
Cognitively normal elderly
Most cognitively healthy normal controls (NC) do not
show appreciable amyloid tracer binding (Figure 1).
Elevated PIB binding is found in 10 to 30% of NC [16,17],
however, and this is similar to observed rates of amyloid
pathology in autopsy studies of normal aging . In
some cases, the extent and distribution of amyloid
pathology in NC is indistin guishable from that found in
AD . Increasing age and the presence of the apo-
lipoprotein E ε4 allele (ApoE ε4) are the major predictors
of PIB-positivity in NC [17,20]. Indeed, PIB binding is
found in 18% or less of subjects below the age of 70, in
26% of individuals aged 70 to 79 years, and in 30% of
those aged 80 to 89 years. ApoE ε4 increases the overall
prevalence of positive scans from 21% in noncarriers to
49% in carriers, and shows dose and age eff ects. PIB-
positivity in NC has also been asso ciated with a family
history of AD, and with subjective cognitive impairment
[21,22]. 18F fi ndings in NC have largely been in agreement
with PIB fi ndings showing similar prevalence, and
relationships with age and ApoE [9-11,23].
Th e signifi cance of a positive amyloid scan in a cogni-
tively normal individual is uncertain. Some studies have
found negative correlations between PIB and episodic
memory in this population [16,24], while other studies
found no diff erences across cognitive measures between
PIB-positive and PIB-negative controls . More consis-
tently, cross-sectional studies have found AD-like struc-
tural and functional brain changes in PIB-positive NC,
such as hippocampal and temporo-parietal atrophy
[24,26] and decreased resting-state connectivity in the
default mode network [27,28]. Two retrospective studies
reported an association between PIB-positivity and
declining cognition [29,30]. In the largest prospective
cohort, PIB-positivity was associated with declining
memory and visuospatial performance , and was the
strongest predictor of functional decline (conversion
from clinical dementia rating of 0 to 0.5 or 1) . Th ese
cross-sectional and early longitudinal data have strength-
ened the notion that many (although probably not all)
PIB-positive NC are in a preclinical phase of AD , but
this hypothesis requires further longitudinal investigation.
From a diagnostic perspective, the signifi cant baseline
rate of amyloid-positive NC emphasizes that amyloid-
positivity is not synonymous with AD, and that amyloid
scans cannot be interpreted in lieu of a detailed clinical
evaluation. Th e true baseline rate of amyloid positivity in
the general population is diffi cult to estimate, since
current data are based on highly selected convenience
cohorts that are probably enriched for AD. Given the
strong association between age and PIB, it is likely that
the positive predictive value of amyloid PET will be
higher in younger patients. At present there is no clinical
indication for amyloid imaging in cognitively normal
individuals. But this will remain an area of active research
in coming years, particularly with the advent of amyloid
lowering therapies which might be most eff ective if
initiated in the presymptomatic disease stage .
Mild cognitive impairment
Current data suggest that amyloid imaging provides
prognostic information in patients with mild cognitive
impairment (MCI), presumably by identifying patients
with underlying AD pathology [35,36]. As a group, 52 to
87% of MCI patients show elevated PIB binding in a
similar regional distribution to AD [16,37]. Patients
meet ing criteria for MCI of the amnestic subtype may be
more likely to be PIB-positive than patients with non-
amnestic presentations . 18F tracer studies report
similar fi ndings, with positive scans found in 45 to 60% of
MCI patients [10,11,23].
In longitudinal studies, 1-year conversion rates to AD
range from 33 to 47% in PIB-positive MCI subjects versus
virtually no conversions in PIB-negative subjects [38,39].
In the largest longitudinal eff ort to date , authors
compared baseline amyloid deposition between MCI
converters and nonconverters in 31 MCI subjects
followed over 3 years. Overall, 55% of MCI subjects had
increased PIB retention at baseline. Th e overall con ver-
sion rate was 82% in those with increased PIB uptake, but
only 7% in PIB-negative subjects. Forty-seven per cent of
PIB-positive subjects converted within 1 year, and these
early converters showed higher tracer retention in the
anterior cingulate and frontal cortex than late converters.
Altogether, PIB-positive patients with MCI of the
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
Page 2 of 11
amnestic subtype are likely to have early AD, and amyloid
imaging will probably have an important role in risk
stratifi cation and selection of patients who may benefi t
from disease-specifi c therapies.
While amyloid PET is likely to predict whether a
patient will convert from MCI to AD, structural/
functional imaging and cognitive tests may be better
predictors of when an individual will convert . Th is
hypothesis is based on a model in which amyloid aggre-
gation is an early event in AD that reaches a relative
plateau even at the MCI stage, while downstream bio-
markers measure neuronal loss and dysfunction, and
cognitive measures are more dynamic at the symptomatic
disease stage . New consensus diagnostic guidelines
for MCI make a distinction between biomarkers of Aβ
deposition (amyloid PET or cerebrospinal fl uid (CSF)
Aβ1–42 levels) and biomarkers of neuronal injury (for
example, CSF tau, hippocampal/medial temporal atrophy
on MRI, hypo meta bolism on FDG-PET) . Biomarkers
from both categories are used in conjunction with core
clinical criteria to assess the likelihood that MCI is due to
under lying AD. If both Aβ and neuronal injury markers
are positive, a diagnosis of MCI due to AD-high
likelihood can be made. Conversely, if markers from both
categories are negative, MCI is considered unlikely due to
AD. If one marker is positive and the other untested, the
likelihood of AD is intermediate – while biomarkers are
considered uninformative if they provide confl icting
Stratifying MCI patients into those with and without
underlying AD may represent the major clinical use of
amyloid imaging. MCI is a common condition, but
clinical certainty regarding the underlying histopathology
is low (as evidenced by the signifi cant percentage of
classical MCI patients of the amnestic subtype who are
PIB-negative). As with studies of normal aging, the
generalizability of MCI studies based on highly selected
research cohorts is questionable because these cohorts
are enriched for AD and often exclude patients with
comorbid illnesses that impact cognition (for example,
cerebrovascular disease, major organ failure). Amyloid
imaging will also be helpful in selecting MCI patients for
clinical trials of AD-specifi c treatments initiated at the
Alzheimer’s disease and variants
Most studies have found that PIB-PET has very high (90%
or greater) sensitivity for AD [17,42]. Tracer binding is
diff use and symmetric, with high uptake consistently
found in the prefrontal cortex, precuneus and posterior
cingulate cortex, followed closely by the lateral parietal,
lateral temporal cortex, and striatum (Figure 1). Th is
pattern closely mirrors the distribution of plaques found
at autopsy . Similar to what has been reported in NC
and MCI, amyloid aggregation appears to be higher in
ApoE ε4 carriers  – although this association is not
always found in patients at the dementia stage .
Correlations between amyloid load and cognitive
measures or disease severity are generally weak or absent
[16,46]. Longitudinal studies in AD are relatively few and
have off ered confl icting results, with some studies report-
ing minimal longitudinal change [47,48] and others
reporting average annual increases of up to 5% in AD
patients . Regardless of whether PIB binding plateaus
or continues to increase slowly at the dementia phase,
brain atrophy and hypometabolism accelerate at this
phase and correlate more robustly with disease severity
and clinical progression [25,46].
Few studies have applied amyloid imaging to atypical
clinical presentations of AD. One study demonstrated the
feasibility of detecting AD pathology in middle-age
persons with Down’s syndrome . PIB-PET was used
to demonstrate that amyloid deposition is more common
in the logopenic variant of primary progressive aphasia
(PPA) than in nonfl uent or semantic variants [50,51],
supporting the hypothesis that the logopenic variant of
PPA is predictive of underlying AD. Several studies have
detected high PIB binding in patients with posterior
cortical atrophy, a visuospatial/biparietal clinical syndrome
often caused by AD [52-54]. Although single case reports
and small series initially reported atypical binding
patterns in PPA and posterior cortical atrophy , larger
series have found a diff use binding pattern in these
syndromes that is indistinguishable from typical AD and
dissociated from the focal structural and metabolic
signatures of these syndromes (see PIB and FDG in AD
vs. logopenic variant PPA in Figure 1) [50,51,53,54].
Similarly, a study comparing PIB binding in early and late
age-of-onset AD found that diff erences in cognitive
profi les (more global defi cits in early-onset AD, and
restricted amnesia in late-onset AD) could not be
explained by the distribution or burden of PIB, which was
identical in the two groups .
New AD diagnostic guidelines adopt a similar frame-
work to the new MCI guidelines and distinguish between
biomarkers of Aβ deposition and neuronal injury .
Clinical and biomarker information is used in con-
junction to modify the probability of underlying AD
pathophysiology. Th ree main categories are proposed:
probable AD dementia, possible AD dementia (atypical
clinical presentation), and probable or possible AD
dementia with evidence of AD pathophysiological process.
In typical clinical presentations, if both categories of
biomarkers are positive, the likelihood of AD patho-
physiology is considered high. If only one of the two
categories is positive, then the probability is intermediate.
Atypical clinical presentations are considered at high
probability of an AD pathophysiological process if both
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
Page 3 of 11
categories of biomarkers are positive, although a second
etiology cannot be excluded. Finally, dementia is con-
sidered unlikely due to AD when both categories of
biomarkers are negative.
Amyloid imaging will probably not add value to the
diagnostic work-up of patients with straightforward
clinical AD, as these patients are very likely to have
positive scans. Th is technique is likely to be useful in
patients with focal cortical syndromes such as PPA and
posterior cortical atrophy, as these are pathologically
heterogeneous syndromes that are variably associated
with underlying AD. Similarly, amyloid PET could be
useful in patients with early age-of-onset dementia, as
these patients often present with atypical symptoms (for
example, executive, behavior, language and visuospatial
rather than memory), and the main alternative cause of
dementia in this age group is frontotemporal lobar
degeneration (FTLD), a non-Aβ disease. Th e low rate of
amyloid-positive non demented individuals in this age
group will increase the positive predictive value of
Cerebral amyloid angiopathy and vascular dementia
PIB binds to vascular amyloid deposits in animal models
and postmortem human tissue [2,4,6]. Nondemented
patients with cerebral amyloid angiopathy show high PIB
binding compared with controls . Although overall
PIB binding is lower than in AD, cerebral amyloid
angiopathy patients show a higher occipital-to-global PIB
ratio, concordant with the occipital predilection of
cerebral amyloid angiopathy at autopsy . PIB may be
useful for stratifying patients with microhemorrhages
into those with underlying cerebral amyloid angiopathy
and those in which hemorrhages are due to small-vessel
vasculopathy, particularly when the anatomic distribution
of hemorrhages is ambiguous (for example, both lobar
and deep gray matter). Th is distinction may impact
decisions regarding anticoagulation. It may also be
important to distinguish AD patients with and without a
signifi cant burden of cerebral amyloid angiopathy, as the
latter may be at higher risk for complications from
amyloid modifying therapies . It is not yet clear
whether PIB will be useful for this purpose (for example,
based on occipital to global binding ratios) or add value
to MRI sequences that are sensitive to microhemorrhages
Vascular dementia can be diffi cult to diff erentiate from
AD on clinical grounds . Th e two share risk factors,
are often comorbid, and may interact biologically. Few
studies have applied amyloid PET to patients with
suspected vascular dementia. One study found that 69%
of patients clinically diagnosed with subcortical vascular
Figure 1. Amyloid tracer binding. Typical 11C-labeled Pittsburgh Compound B (PIB) binding and 18F-fl uorodeoxyglucose (FDG) hypometabolism
patterns in normal controls (NC), Alzheimer’s disease (AD), logopenic variant of primary progressive aphasia (lvPPA), behavioral variant
frontotemporal dementia (bvFTD), and semantic variant of primary progressive aphasia (svPPA). DVR, distribution volume ratio; SUVR, standardized
uptake value ratio.
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
Page 4 of 11
dementia were PIB-negative . Younger age and a
greater number of lacunes predicted a negative PIB scan.
Another study found high PIB binding in 40% of patients
with post-stroke dementia . PIB-positive post-stroke
patients declined more rapidly on the Mini-Mental State
Examination (MMSE) than did PIB-negative patients.
Altogether, amyloid PET will probably have a clinical role
in identifying cognitively impaired patients with high
vascular burden who also have comorbid AD (and thus
may benefi t from AD treatments), and will further our
understanding of how AD and vascular disease interact
and contribute to cognitive decline in the aging brain.
Parkinson’s disease and dementia with Lewy bodies
Th e percentage of PIB-positive scans in patients with
dementia with Lewy bodies (DLB) has ranged between
30 and 85% in small case series [63-67]. Similar variations
have been reported in Parkinson’s disease dementia (15
to 100% PIB-positive). PIB scans were negative in two
patients with multiple system atrophy , and
fl orbetaben-PET was negative in fi ve patients with
Parkinson’s disease without dementia and positive in 29%
of clinically diagnosed DLB patients . Th ese diff er-
ences may be explained both by cohort factors and by the
method of defi ning scan positivity (for example,
qualitative vs. quantitative, thresholds, and so forth).
Th e pattern of binding in DLB and Parkinson’s disease
dementia is similar to AD, although overall binding is
lower with higher intersubject variability. Most studies
have found higher amyloid plaques in DLB than in
Parkinson’s disease dementia or nondemented Parkin-
son’s disease patients, and in some studies PIB-positivity
was asso ciated with greater cognitive defi cits and more
rapid disease progression . Overall, these fi ndings are
concordant with autopsy-based studies on the frequency
and impact of Aβ plaques in DLB and Parkinson’s disease
dementia . In vitro and postmortem studies suggest
that the in vivo PET signal in synuclein disorders refl ects
PIB binding to Aβ deposits rather than to Lewy bodies
[2,5]. Given the high frequency of amyloid plaques and
generally high rates of positive amyloid scans in DLB, it is
unlikely that amyloid PET will be helpful in diff erentiating
DLB from AD. Amyloid PET may diff erentiate Parkin-
son’s disease or Parkinson’s disease dementia from AD,
but this diff er en tiation can usually be accomplished
clinically. Further work is needed to determine whether
amyloid PET can provide prognostic information in
Frontotemporal lobar degeneration spectrum disorders
FTLD is an umbrella term used for disorders associated
with neurodegeneration of the frontal and anterior
temporal lobes . Clinical syndromes that fall in the
FTLD spectrum include the behavioral variant of
fronto temporal dementia (bvFTD), frontotemporal
dementia with motor-neuron disease, and the semantic
and non fl uent variants of PPA [71,72]. Histopathology in
FTLD is heterogeneous, with most cases featuring tau
(Pick’s disease, corticobasal degeneration and progressive
supra nuclear palsy), TDP-43 or fused-in sarcoma protein
inclusions . FTLD and AD are the leading causes of
early age-of-onset dementia, occurring with similar
frequency in patients presenting younger than the age of
65 . Distinguishing the two during life can be chal-
leng ing due to clinical and anatomic overlap, and mis-
diagnosis rates of 10 to 40% are reported even in expert
Diff erentiating AD from FTLD is an important clinical
use for amyloid PET, since Aβ plaques are not part of the
FTLD pathologic spectrum, and the diff erential diagnosis
comes up in young patients in whom age-related amyloid
aggregation is less common. Small case series reported
low rates of PIB (0 to 15%) and fl orbetaben-positivity
(9%) in FTLD (see bvFTD and semantic variant PPA in
Figure 1) [11,67,76]. Diff erentiating AD and FTLD was
the focus of the largest study on the diagnostic utility of
amyloid PET published to date . In 62 AD patients
and 45 FTLD patients matched for age and disease
severity, PIB visual reads had a higher sensitivity for AD
than FDG-PET (89.5% vs. 77.5%), with similar specifi city
(83% vs. 84%). When scans were classifi ed quantitatively,
PIB had higher sensitivity (89% vs. 73%) while FDG had
higher specifi city (83% vs. 98%). PIB outperformed FDG
in classifying 12 patients with known histopathology
(97% vs. 87% overall accuracy). PIB visual reads also
showed higher inter-rater reliability and agreement with
quantitative classifi cation than FDG, suggesting it was
the more accurate and precise technique.
Corticobasal syndrome (CBS) is sometimes included
under the FTLD umbrella because of considerable
clinical and pathologic overlap . While most cases of
clinical CBS are associated with FTLD pathology
(although not necessarily corticobasal degeneration), 25
to 50% of patients are found to have AD as the causative
pathology postmortem [75,77,78]. Amyloid PET would
theoretically be useful in identifying CBS patients with
underlying AD, but clinical studies are lacking. In our
center PIB was positive in a patient with CBS found to
have AD/DLB at autopsy (see Figure 2, Case 4), while PIB
scans were negative in two CBS patients with patho-
logically confi rmed corticobasal degeneration (unpub-
Clinical symptoms and imaging fi ndings suggestive of
normal pressure hydrocephalus (NPH) overlap with those
found in neurodegenerative diseases, and AD pathology
is found in a signifi cant proportion of patients clinically
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
Page 5 of 11
diagnosed with NPH . In some studies, the presence
of AD pathology predicted poor response to shunting
, prompting a few centers to routinely obtain cortical
biopsies prior to shunting suspected NPH . Two
studies have compared PIB-PET  or fl utemetamol-
PET  with frontal biopsy results in patients with
suspected NPH. Combined, PET scans were positive in
eight out of nine biopsy-positive patients, and negative in
eight out of eight biopsy-negative cases. Strong corre la-
tions were found between regional tracer uptake and
quantitative measures of Aβ in both studies. Further work
is needed to determine the prognostic value of amyloid
PET in the evaluation of NPH, and to study the proposed
biological relationships between AD and NPH .
PIB scans were negative in three small series featuring a
range of prion disorders, including sporadic Creutzfeldt–
Jakob disease, variant Creutzfeldt–Jakob disease, and a
range of prion protein mutations [83,84]. Genetic prion
disease can occasionally present insidiously and mimic
AD, while DLB can present as a rapidly progressive
dementia and be mistaken for Creutzfeldt–Jakob disease.
However, prion disease can usually be distinguished from
Aβ-associated diseases on clinical grounds and based on
characteristic MRI fi ndings .
A study of PIB in HIV-positive individuals found that
cognitively impaired patients with HIV do not show high
PIB binding (although some showed low levels of CSF
Aβ1–42), suggesting that PIB may distinguish HIV dementia
from AD, a diagnostic dilemma that will become
increasingly relevant with an aging HIV-positive
Amyloid PET applied to clinically challenging cases
We have applied amyloid and FDG-PET to over 200
patients followed in dementia research cohorts at the
University of California San Francisco Memory and
Aging Center as part of an ongoing study on the utility of
these techniques in diff erential diagnosis. Figure 2 shows
PIB and FDG scans from four clinically challenging cases,
described in the vignettes below.
Case 1 is an 89-year-old man with 8 years of progressive
memory loss, executive dysfunction, behavioral changes,
and an MMSE of 29. MRI showed severe hippocampal
atrophy as well as signifi cant subcortical white matter
disease and a number of lacunes. Clinical diagnosis was
mixed AD/vascular dementia. FDG showed bifrontal
hypometabolism sparing the temporo-parietal cortex,
while PIB revealed diff use cortical binding. Autopsy
indicated high-likelihood AD (CERAD frequent/Braak
stage 6) and moderate subcortical ischemic vascular
disease. In this case, FDG alone could have led to a
misdiagnosis of pure vascular disease or bvFTD (the
latter less likely based on age), and treatment with a
cholinesterase inhibitor may not have been off ered.
Figure 2. Clinically challenging cases imaged with 11C-labeled Pittsburgh Compound B and 18F-fl uorodeoxyglucose. Autopsy diagnosis is
available in three cases. See text for a description of the cases. FDG, 18F-fl uorodeoxyglucose; PIB, 11carbon-labeled Pittsburgh Compound B; DVR,
distribution volume ratio; SUVR, standardized uptake value ratio.
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
Page 6 of 11
Case 2 is a 55-year-old man with 9 years of profound
behavioral changes including compulsive behaviors,
disinhibition, socially inappropriate behavior, and impair-
ment in executive, memory, and visuospatial functions
(MMSE = 16). He was clinically diagnosed with bvFTD.
FDG showed bilateral frontal and temporo-parietal
hypo metabolism, while PIB revealed diff use cortical
binding. Pathology is not available. In this case, PIB
provides a useful tiebreaker in favor of AD in an early-
onset dementia patient in whom clinical features and
FDG-PET are ambiguous between AD and FTLD. A
cholinesterase inhibitor was subsequently started.
Case 3 is a 70-year-old woman presenting with non-
fl uent variant PPA (MMSE = 28). FDG showed focal left
frontal hypometabolism, while PIB was unexpectedly
positive. On autopsy the patient was found to have both
Pick’s disease and high-likelihood AD (CERAD frequent/
Braak 5). Th is case demonstrates that while PIB can
accurately detect AD pathology, a positive amyloid scan
does not rule out comorbid non-Aβ pathology, which in
this case was FTLD, as predicted based on the clinical
presentation and FDG-PET pattern.
Case 4 is a 68-year-old man with 6 years of progressive
asymmetric left-sided apraxia, Parkinsonism, dystonia,
tremor, and myoclonus. Levodopa treatment was un-
helpful. Cognitive decline was characterized by defi cits in
executive and visuospatial functions, episodic memory
and language (MMSE = 19). Visual hallucinations
emerged later in the course. Clinical diagnosis was CBS.
FDG revealed asymmetric right posterior frontal and
temporo-parietal hypometabolism. Pathological diagnosis
was mixed high-likelihood AD (CERAD frequent/Braak 6)/
intermediate-likelihood DLB. In this case, PIB correctly
predicted underlying AD in a patient with a clinical
syndrome (CBS) associated with varied histopathology.
Amyloid PET in clinical practice: unresolved
questions and recommendations
Th ere are many unknowns that could impact the
diagnostic utility of amyloid PET. First, the sensitivity and
specifi city compared with pathology are not yet well
defi ned. Technical and patient factors that could lead to
false positives and false negatives are not clear. PIB binds
to both diff use and neuritic plaques  (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 off er additional diagnostic
information. Studies examining inter-rater and intra-
rater reliability of visual interpretations are few, and the
optimal quantitative threshold for defi ning a positive
scan has not yet been defi ned . Also not yet
estab lished 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)  or
genetic variables such as the ApoE ε4 genotype.
Signifi cantly, the relationship between amyloid and
dementia is weaker in older versus younger individuals
. Th e 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).
Th e ideal combination of biomarkers in the evaluation
of dementia will probably depend on the specifi c clinical
scenario. In general, the approach introduced in the new
AD diagnostic guidelines (one marker specifi c for Aβ,
another specifi c for neurodegeneration to establish AD
as the probable pathophysiology) has face validity .
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  or FDG [89,90],
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 , how CSF AD biomarkers and amyloid
imaging compare in diff erentiating 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 [20,92], rendering CSF potentially
more sensitive for early detection but less specifi c in
determining the cause of dementia. Th e lack of specifi city
may be overcome, however, by applying a ratio of Tau/
Aβ1–42 or phospho-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 . 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
diff erentiating AD and DLB) .
Ultimately, to be widely adopted a diagnostic test needs
to have a signifi cant impact on patient management and
outcomes, and to be cost-eff ective. Few studies have
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
Page 7 of 11
examined these points with regard to amyloid imaging.
In our clinic, PIB results have had implications for treat-
ment, mainly aff ecting 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 benefi t
are currently not treated (for example, MCI due to AD)
based on negative clinical trials that may have been
confounded by biological heterogeneity . Such
decisions would be more rational if amyloid PET was
applied in the right circumstances, and this could result
in cost saving. Th e more immediate impact of amyloid
imaging will be in improving clinical trial design by
enrolling patients based on biological, rather than
clinical, phenotype. Th is is a necessary fi rst step for the
development and testing of disease-specifi c therapies.
Initial studies have found that requiring a positive
molecular biomarker for inclusion will render AD clinical
trials more effi cient and less costly, especially in early
disease stages . In fact, a positive amyloid scan may
be the primary inclusion criterion for a study focused on
Recommendations for potential clinical applications of
amyloid PET are provided in Table 1. Th ese 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.
Th e recom menda tions 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
diff erentiating Aβ from non-Aβ causes of dementia in
scenarios in which this distinction is clinically challeng-
ing – 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 microhemor rhages); and, fi nally,
some very important applications of amyloid PET should
be restricted to research studies (for example, scanning
asymptomatic or minimally sympto matic patients).
While amyloid imaging has produced an impressive body
of research in a short time, studies of practical clinical
applications for this technology lag far behind studies
with more biological objectives. Since clinical use is now
feasible and will probably be approved by regulatory
agencies in the near future, it is imperative that the
diagnostic performance, added clinical value, and cost-
eff ectiveness of this technique be studied systematically
Table 1. Clinical and research utility of amyloid imaging
Potential clinical utility
1. Determine whether MCI is due to AD
2. Diff erentiate AD from non-AD dementia (for example, frontotemporal lobar degeneration), particularly in early age-at-onset patients
3. Determine whether AD copathology is present in patients with cognitive impairment and other known neurologic disease (for example, Parkinson’s
disease, stroke/vascular disease, multiple sclerosis, epilepsy, HIV)
4. Diff erentiate AD from nondegenerative cognitive decline (for example, depression, substance abuse)
5. Determine whether AD is present in patients with advanced dementia and no reliable history
6. Identify whether AD is present in focal cortical syndromes (for example, posterior cortical atrophy, primary progressive aphasia, corticobasal syndrome)
7. Diff erentiate cerebral amyloid angiopathy from intracranial hemorrhage due to small-vessel vasculopathy
Unlikely to have clinical utility
1. Initial investigation of cognitive complaints (in the absence of a detailed neurologic evaluation and cognitive testing)
2. Diff erentiate AD from other amyloid-beta-associated dementia (for example, dementia with Lewy bodies, cerebral amyloid angiopathy)
3. Diff erentiate between AD clinical variants (for example, classic amnestic AD vs. posterior cortical atrophy or logopenic variant primary progressive aphasia)
4. Diff erentiate between non-AD causes of dementia (for example, molecular subtypes of frontotemporal lobar degeneration)
Utility for research only
1. Testing and longitudinal follow-up of asymptomatic or subjective cognitive impairments not meeting MCI criteria or at-risk individuals (for example, gene
mutation carriers, family history of AD, apolipoprotein E ε4 allele)
2. Selection of candidates for anti-amyloid treatment trials (AD, MCI, preclinical)
3. Study of the natural evolution of amyloid burden and its role in the pathophysiology of AD and other dementias
4. Potential surrogate marker for anti-amyloid therapies
In all situations, structural imaging using magnetic resonance imaging is recommended to rule out space-occupying lesions, infl ammation, or other confounding
conditions. AD, Alzheimer’s disease; MCI, mild cognitive impairment.
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
Page 8 of 11
and in populations more representative of real clinical
practice. With all its limitations, amyloid imaging repre-
sents a major breakthrough in the evaluation of dementia
that will doubtlessly translate into better clinical care,
and will ultimately help guide the development of
molecular-based therapies for these devastating illnesses.
Aβ, amyloid beta; Aβ1–42, amyloid beta 1–42 peptide; AD, Alzheimer’s
disease; ApoE ε4, apolipoprotein E ε4 allele; bvFTD, behavioral variant of
frontotemporal dementia; 11C, carbon-11; CBS, corticobasal syndrome;
CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; CSF,
cerebrospinal fl uid; DLB, dementia with Lewy bodies; 18F, fl uorine-18;
FDG, fl uorodeoxyglucose; FTLD, frontotemporal lobar degeneration; MCI,
mild cognitive impairment; MMSE, Mini-Mental State Examination; MRI,
magnetic resonance imaging; NC, normal controls; NPH, normal pressure
hydrocephalus; PIB, Pittsburgh Compound B; PET, positron emission
tomography; PPA, primary progressive aphasia.
RL Jr declares that he has no competing interests. GDR received
consulting fees from GE Healthcare, and receives grant support from Avid
radiopharmaceuticals, a wholly-owned subsidiary of Eli Lilly and Company.
Both companies are developing amyloid PET tracers for commercial purposes.
The authors would like to thank Dr WJ Jagust and Dr S Villeneuve for their
review of the manuscript prior to publication. GDR is supported by grants
from the National Institute on Aging (K23-AG031861) and the John Douglas
French Alzheimer’s Foundation.
Published: 10 November 2011
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Cite this article as: Laforce R Jr, Rabinovici GD: Amyloid imaging in
the diff erential diagnosis of dementia: review and potential clinical
applications. Alzheimer’s Research & Therapy 2011, 3:31.
Laforce and Rabinovici Alzheimer’s Research & Therapy 2011, 3:31
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