Research

Case Report/Case Series

Does a Positive Pittsburgh Compound B Scan in a Patient
With Dementia Equal Alzheimer Disease?
Simon Ducharme, MD, MSc; Marie-Christine Guiot, MD, FRCPC;
James Nikelski, PhD; Howard Chertkow, MD, FRCPC

IMPORTANCE The clinical role of amyloid brain positron emission tomographic imaging in the

diagnosis of Alzheimer disease is currently being formulated. The specificity of a positive
amyloid scan is a matter of contention.
OBSERVATIONS An 83-year-old Canadian man presented with a 5-year history of
predominantly short-term memory loss and functional impairment. Clinical evaluation
revealed significant, gradually progressive short-term memory loss in the absence of any
history of strokes or other neuropsychiatric symptoms. The patient met clinical criteria for
probable Alzheimer disease but had a higher than expected burden of white matter disease
on magnetic resonance imaging. A positron emission tomographic Pittsburgh Compound B
scan was highly positive in typical Alzheimer disease distribution. The patient died of an
intracerebral hemorrhage 6 months after the assessment. Autopsy revealed cerebral amyloid
angiopathy in the complete absence of amyloid plaques or neurofibrillary tangles.
CONCLUSIONS AND RELEVANCE This patient demonstrates that a positive Pittsburgh
Compound B scan in a patient with clinical dementia meeting criteria for probable Alzheimer
disease is not proof of an Alzheimer disease pathophysiological process. A positive Pittsburgh
Compound B scan in typical Alzheimer disease distribution in a patient with dementia can be
secondary to cerebral amyloid angiopathy alone.
JAMA Neurol. 2013;70(7):912-914. doi:10.1001/jamaneurol.2013.420
Published online May 20, 2013.

C

arbon 11 ([11C])–labeled Pittsburgh Compound B (PiB) has
been developed as a positron emission tomography (PET)
ligand that binds to fibrillar β-amyloid.1 The PiB PET scans
are positive in 95% of patients with Alzheimer disease (AD) and
about 60% of patients with mild cognitive impairment.2,3 Given
the high specificity of PiB in cases of dementia as well as the US
Food and Drug Administration’s approval of similar amyloid PET
imaging for clinical use (florbetapir F 18 injection [Amyvid]), this
test is bound to be interpreted as an AD test despite reservations
expressed by the scientific community and statements by the
company that “a positive scan does not establish a diagnosis of
Alzheimer’s disease or other cognitive disorder.”2,4 It is therefore
crucial for clinicians to have a better sense of the sensitivity and
specificity of this test. Herein, we report the first case, to our
knowledge, of a patient with a clinical history suggestive of AD
with a positive PiB scan who did not have any evidence of amyloid plaques or neurofibrillary tangles on autopsy.

Report of a Case
An 83-year-old man with a university-level education was assessed at the Memory Clinic of the Jewish General Hospital for
912

Author Affiliations: Department of
Neurology, Massachusetts General
Hospital and McLean Hospital,
Harvard University, Boston
(Ducharme); Department of
Psychiatry, McGill University,
Montreal, Quebec, Canada
(Ducharme); Department of
Neurology and Neurosurgery, McGill
University, Montreal, Quebec, Canada
(Guiot, Chertkow); Lady Davis
Institute for Medical Research, Jewish
General Hospital, McGill University,
Montreal, Quebec, Canada (Nikelski,
Chertkow).
Corresponding Author: Howard
Chertkow, MD, FRCPC, Lady Davis
Institute for Medical Research, Jewish
General Hospital, McGill University,
3755 Cote Ste-Catherine Rd,
Montreal, QC H3T-1E2, Canada
(howard.chertkow@mcgill.ca).

a 5-year history of memory loss. He was physically healthy with
no history of strokes, hypertension, coronary artery disease, or
psychiatric disorder. Familial history was negative for dementia.
Memory decline had begun insidiously at age 78 years, with
gradual progression over time. Instrumental activities of daily
living had been impaired since age 80 years. He had stopped
driving and had become more withdrawn. There was no significant change in personality or other neuropsychiatric symptoms suggestive of Lewy body dementia or frontotemporal
dementia.
Findings on physical examination including blood pressure and general neurological examination were entirely within
normal limits. He had no primitive reflexes. There was no sign
of parkinsonism. On cognitive examination, the Montreal Cognitive Assessment score was 17 of 30, including 0 of 5 on delayed recall.5 The Mini-Mental State Examination score was 23
of 30,6 with impairment in delayed verbal memory and orientation but relatively preserved attention and language. There
were impairments in executive function, clock drawing, and
calculation. A complete neuropsychological evaluation completed in February 2010 confirmed this profile.
The dementia biochemical workup findings were normal
except for mild hyperglycemia (fasting glucose, 127.9 mg/dL;

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Pittsburgh Compound B Scan and Alzheimer Disease

Case Report/Case Series Research

Figure 1. Magnetic Resonance Image and Positron Emission Tomographic Scan
A

B

A, Axial T2-weighted magnetic resonance imaging showing prominent
periventricular white matter changes. B, Positive carbon 11–labeled Pittsburgh
Compound B positron emission tomographic scan showing β-amyloid (light

color) in typical Alzheimer disease distribution, superimposed on a
3-dimensional rendering of the patient’s structural magnetic resonance image
(dark color).

to convert to millimoles per liter, multiply by 0.0555). A computed tomographic scan showed moderate diffuse atrophy with
periventricular white matter hypodensities. Given the clinical presentation and limited vascular risk factors, the patient
was diagnosed as meeting criteria for probable AD7 in addition to type 2 diabetes mellitus. Treatment was begun with the
cholinesterase inhibitor donepezil hydrochloride, 10 mg/d, with
little obvious change in cognition at follow-up.
The patient consented to involvement in research studies of
natural history, including neuroimaging. A T1-weighted magnetic resonance image and a T2-weighted fast spin-echo magnetic resonance image were acquired on a 1.5-T scanner using
magnetization-prepared rapid acquisition with gradient-echo
pulse sequences with 1.2-mm-thick sagittal slices. This demonstrated prominent confluent white matter changes (Figure 1).
There was no clear evidence of infarction or microbleeds, although gradient-echo sequence was not carried out. Imaging
with PET using [11C]PiB was carried out at the Montreal Neurological Institute using 15-mCi injection over 20 seconds, a waiting period of 50 minutes, and then image acquisition over 40
minutes. The PET data were acquired on a Siemens/CTI ECAT
HR+ scanner in 3-dimensional imaging mode (63 parallel
planes). The standardized uptake value ratio was determined by
normalizing tissue radioactivity concentration for each of 48
brain regions against radioactivity in cerebellar gray matter. The
PiB visual rating was strongly positive, with ligand distribution
in a pattern typical for AD. The standardized uptake value ratio
was also positive at 1.83 (our cutoff for a positive scan is a standardized uptake value ratio of 1.24), with a large amyloid distribution typical for AD (Figure 1). In the new lexicon, the positive
amyloid imaging (but unusual magnetic resonance imaging results) was taken to give intermediate biomarker support to the
clinical diagnosis of probable AD.3
Six months later, the patient presented with sudden collapse
and left hemiparesis. A repeated cerebral computed tomographic

scan showed massive right intracerebral hemorrhage compatible with amyloid angiopathy. The patient died 4 hours later.
At autopsy, there was a right intracerebral hemorrhage extending from the right superotemporal region to the midline and
breaking into the ventricular system at the level of the amygdala.
There were numerous recent hemorrhages in the midbrain and
pons. No old cerebral infarctions were noted. Microscopic examination showed no senile plaques or neurofibrillary tangles in any
part of the brain and no microscopic evidence even suggestive
of AD. Indeed, the prominent microscopic finding was of a diffuse cerebral amyloid angiopathy (CAA) affecting all the lobes
with a predilection for the occipital lobe (Figure 2). The striking
absence of amyloid plaques and neurofibrillary tangles, hallmarks
of AD-type histological changes, excluded the diagnosis of AD.
Therefore, the final pathological diagnosis was vascular dementia secondary to CAA.

Discussion
Cerebral amyloid angiopathy is characterized by deposition of
amyloid in the media and adventitia of small and medium-sized
blood vessels of the cerebral cortex and leptomeninges.8 It is frequently asymptomatic, but it constitutes an important cause of
primary intracerebral hemorrhage in elderly individuals.8 Incidence increases with age, and some degree of CAA has been
found in up to 36% of brains of autopsied individuals older than
60 years.9 This is about twice the number of individuals with clinical AD dementia or “prodromal AD.” Amyloid deposits seen in
the sporadic form of CAA are similar to the material found in senile plaques of AD. About 25% of subjects with AD have moderate to severe CAA on autopsy, but fewer than 50% of patients with
CAA meet pathological criteria for AD.8,10
According to the recent National Institute on Aging–
Alzheimer’s Association diagnostic criteria, this patient would

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Research Case Report/Case Series

Pittsburgh Compound B Scan and Alzheimer Disease

Figure 2. Postmortem Immunohistochemistry for β-Amyloid
in the Occipital Lobe

1 mm

Absence of positive amyloid plaques and presence of numerous
intraparenchymal cortical and subarachnoid vessels demonstrated strong
positivity for β-amyloid (clone 6F/3D [Dako Corp], original magnification ×20).

have been classified prior to his hemorrhagic stroke as having
probable AD dementia by clinical criteria, with intermediate
probability of the AD pathophysiological process (evidence of
β-amyloid on imaging without available evidence of neuronal injury).3 The autopsy revealed that both clinical criteria and
PiB imaging wrongly supported a diagnosis of AD. The only
clinical cue to the correct diagnosis of vascular dementia was
the presence of confluent white matter changes on magnetic
resonance imaging.

ARTICLE INFORMATION
Accepted for Publication: February 14, 2013.
Published Online: May 20, 2013.
doi:10.1001/jamaneurol.2013.420.
Author Contributions: Study concept and design:
Ducharme and Chertkow.
Acquisition of data: Guiot and Chertkow.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Ducharme, Guiot, and
Chertkow.
Critical revision of the manuscript for important
intellectual content: Guiot, Nikelski, and Chertkow.
Statistical analysis: Nikelski.
Obtained funding: Chertkow.
Administrative, technical, and material support:
Guiot.
Study supervision: Chertkow.

It has been demonstrated that PiB binds to amyloid in vessel walls.11,12 Binding of PiB is increased in individuals with CAA
compared with controls, but less so than in subjects with
AD.12,13 The occipital to global uptake ratio tends to be more
pronounced in CAA, paralleling the preferential posterior distribution of cerebral hemorrhages.12,13 There is one published
report of a patient with Lewy body dementia with a positive
PiB scan due to CAA, but the concurrent pathological evidence of amyloid plaques and neurofibrillary tangles complicated this case.11 To our knowledge, we are the first to describe a positive PiB scan in typical AD distribution in a patient
with dementia in the complete absence of significant amyloid plaques and neurofibrillary tangles.
As AD biomarkers become more accessible and even
routinized in dementia and mild cognitive impairment, we
must recognize that a positive PiB scan is not synonymous
with AD in patients with dementia and that positive PiB
results suggestive of AD can be present in CAA, which is a
common brain pathology.9 Indeed, recent US Food and Drug
Administration regulatory guidelines for Amyvid stress that
while a negative scan is useful to exclude the diagnosis of
AD, a positive scan is not a definitive test for AD. The presence of prominent white matter changes on magnetic resonance imaging in the absence of vascular risk factors should
raise the possibility of a CAA diagnosis.14 Because CAA is
often asymptomatic in elderly individuals, we would also
speculate that a certain percentage of cognitively normal
individuals who have positive amyloid PET imaging15 in fact
could have CAA rather than AD.16

2. Rowe CC, Ng S, Ackermann U, et al. Imaging
β-amyloid burden in aging and dementia.
Neurology. 2007;68(20):1718-1725.
3. McKhann GM, Knopman DS, Chertkow H, et al.
The diagnosis of dementia due to Alzheimer’s
disease: recommendations from the National
Institute on Aging-Alzheimer’s Association
workgroups on diagnostic guidelines for Alzheimer’s
disease. Alzheimers Dement. 2011;7(3):263-269.
4. Rabinovici GD, Furst AJ, O’Neil JP, et al. 11C-PIB
PET imaging in Alzheimer disease and
frontotemporal lobar degeneration. Neurology.
2007;68(15):1205-1212.

aging brain, II: the distribution of amyloid vascular
changes. Stroke. 1983;14(6):924-928.
10. Ellis RJ, Olichney JM, Thal LJ, et al. Cerebral
amyloid angiopathy in the brains of patients with
Alzheimer’s disease: the CERAD experience, part
XV. Neurology. 1996;46(6):1592-1596.
11. Bacskai BJ, Frosch MP, Freeman SH, et al.
Molecular imaging with Pittsburgh Compound B
confirmed at autopsy: a case report. Arch Neurol.
2007;64(3):431-434.
12. Johnson KA, Gregas M, Becker JA, et al. Imaging
of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol. 2007;62(3):229-234.

5. Nasreddine ZS, Phillips NA, Bédirian V, et al. The
Montreal Cognitive Assessment, MoCA: a brief
screening tool for mild cognitive impairment. J Am
Geriatr Soc. 2005;53(4):695-699.

13. Ly JV, Donnan GA, Villemagne VL, et al. 11C-PIB
binding is increased in patients with cerebral
amyloid angiopathy-related hemorrhage.
Neurology. 2010;74(6):487-493.

Conflict of Interest Disclosures: Dr Chertkow sits
on an adjudication board for clinical trials for
Bristol-Myers Squibb and has been a speaker and
advisory board member for Pfizer Canada.

6. Folstein MF, Folstein SE, McHugh PR.
“Mini-mental state”: a practical method for grading
the cognitive state of patients for the clinician.
J Psychiatr Res. 1975;12(3):189-198.

14. Greenberg SM, Gurol ME, Rosand J, Smith EE.
Amyloid angiopathy-related vascular cognitive
impairment. Stroke. 2004;35(11)(suppl 1):2616-2619.

Funding/Support: Dr Chertkow is supported by
operating grants from the Canadian Institutes for
Health Research and the Fonds de la recherche en
santé du Québec.
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