In vivo amyloid imaging in autopsy-
confirmed Parkinson disease with dementia
M.A. Burack, MD, PhD
J. Hartlein, MSN
H.P. Flores, MS
L. Taylor-Reinwald, BA
J.S. Perlmutter, MD
N.J. Cairns, PhD
Objective: To investigate the specificity of in vivo amyloid imaging with [11C]–Pittsburgh Com-
pound B (PIB) in Parkinson disease dementia (PDD).
Methods: We performed detailed neuropathologic examination for 3 individuals with PDD who had
PIB PET imaging within 15 months of death.
Results: We observed elevated cortical uptake of [11C]-PIB on in vivo PET imaging in 2 of the 3
cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and
were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2
PIB-positive individuals had abundant diffuse A? plaques but only sparse neuritic plaques and
intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse
plaques, no neuritic plaques, and low neurofibrillary tangle burden.
Conclusions: [11C]–Pittsburgh Compound B (PIB) PET is specific for fibrillar A? molecular pathology
but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease
dementia. The ability to specifically identify fibrillar A? amyloid in the setting of ?-synucleinopathy
makes [11C]-PIB PET a valuable tool for prospectively evaluating how the presence of A? amyloid influ-
AD ? Alzheimer disease; BP ? binding potentials; CDR ? Clinical Dementia Rating; DAT ? dementia of the Alzheimer type;
DLB ? dementia with Lewy bodies; DV ? distribution volume; MMSE ? Mental State Examination; NPI-Q ? Neuropsychiatric
Inventory Questionnaire; PDD ? Parkinson disease dementia; PIB ? Pittsburgh Compound B; UPDRS ? Unified Parkinson’s
Disease Rating Scale.
Individuals with Parkinson disease (PD) are nearly 6 times more likely to develop dementia
than age-matched controls, and the majority of individuals with PD who survive more than 15
years after diagnosis will develop dementia.1,2Clinicopathologic investigations have revealed
heterogeneous histopathology, with Alzheimer disease (AD) pathology (amyloid plaques and
neurofibrillary tangles) present in a subset of individuals with PD dementia (PDD).1When
present, AD pathology is typically found in conjunction with other neuropathologic changes,
including limbic and cortical Lewy bodies and degeneration of subcortical monoaminergic and
cholinergic pathways. The contribution of AD pathology to the pathogenesis of dementia in
the setting of PD is thus uncertain. The presence of AD pathology has been postulated to
influence clinical manifestations of dementia, for example masking features of dementia with
Lewy bodies (DLB) such as hallucinations and fluctuations3,4or influencing the timing of
dementia onset in patients with Lewy body disorders.5
Antemortem evaluation of A? plaque burden by PET imaging using amyloid-specific radiotrac-
ers can potentially clarify the role of these lesions in the pathogenesis of Lewy body–associated
dementias (PDD and DLB). The tracer N-methyl-[11C]2-(4?-methylaminophenyl)-6-
hydroxybenzothiazole (or [11C]-PIB for Pittsburgh Compound-B) has shown great promise for
this purpose, demonstrating rapid diffusion across the blood–brain barrier, high affinity to a
From the Departments of Neurology (M.A.B.) and Pediatrics (M.A.B.), University of Rochester School of Medicine and Dentistry, Rochester, NY;
and Alzheimer’s Disease Research Center (L.T.-R., N.J.C.), Department of Neurology (M.A.B., J.H., H.P.F., L.T.-R., J.S.P., N.J.C.), Department of
Pathology & Immunology (N.J.C.), Program in Physical Therapy (J.S.P.), Department of Radiology (J.S.P.), Program in Occupational Therapy
(J.S.P.), and Department of Anatomy & Neurobiology (J.S.P.), Washington University School of Medicine, St. Louis, MO.
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Michelle
A. Burack, Department of
Neurology and Pediatrics, 601
Elmwood Avenue, Box 673,
University of Rochester Medical
Center, Rochester, NY 14642
Copyright © 2010 by AAN Enterprises, Inc.
single binding site on synthetic A? (Kd ? 4.7
nM), and high affinity to a single binding site
in homogenates of frontal cortex from brains
with AD (Kd ? 1.4 nM).6,7PET images of
[11C]-PIB in individuals with dementia of the
Alzheimer type (DAT) reveal widespread in-
creased tracer uptake in neocortical regions,
with relative sparing of the occipital and sen-
sory/motor cortices and minimal uptake in
the cerebellar cortex.8
In an ongoing cohort study, we have per-
formed [11C]-PIB PET imaging in individuals
tudinal clinical and psychometric assessments.
mortem neuropathologic evaluation. Our pre-
liminary results, reported previously in abstract
form, are consistent with findings of other
investigators,9-11with a subset of individuals
with Lewy body disorders (?20%) demonstrat-
ing elevated cortical [11C]-PIB uptake.12We re-
port here the postmortem neuropathologic
vivo [11C]-PIB PET imaging and subsequently
METHODS Standard protocol approvals, registra-
tions, and patient consents. All study procedures were ap-
proved by Washington University’s Human Research Protection
Office. Prior to enrollment, written informed consent was ob-
tained for all participants. For individuals lacking capacity due to
dementia, a surrogate decision-maker (spouse, first-degree family
member, or health care proxy) provided informed consent and
ongoing assent was obtained from the participant throughout
the study procedures.
Subject selection and clinical assessment. Individuals
were recruited from the greater St. Louis area; there were no
gender or race restrictions. Participants with clinically probable
or definite idiopathic PD (modified United Kingdom PD Brain
Bank criteria13) or DLB14were screened via detailed clinical his-
tory (including review of motor, cognitive, and neuropsychiatric
symptoms, comorbid medical conditions, and medications) and
neurologic examination. Exclusionary criteria included other
conditions that could contribute substantially to the subject’s
motor and/or cognitive impairment, including neurologic (e.g.,
Parkinson-plus disorders other than DLB), psychiatric (e.g., ma-
jor affective disorders, unless cognitive impairment and mood
symptoms were clearly temporally dissociated), or medical con-
ditions (e.g., drug-induced or other delirium). From October
2006 to March 2009, we enrolled 10 healthy elderly control
individuals and 40 individuals with iPD or DLB. Three of the
enrolled participants subsequently died and donated their brains
for the study.
All 3 of the deceased participants met clinical diagnostic cri-
teria for PDD1; none had a known family history of dementia or
PD. Individual histories are provided in appendix e-1 on the
Neurology®Web site at www.neurology.org, and clinical data are
summarized in table 1. Motor symptoms were assessed using the
Unified Parkinson’s Disease Rating Scale (UPDRS) subscale 3
(motor subscale) and Hoehn-Yahr staging while having benefit
from medication (ON state). Levodopa equivalent daily dose
was calculated using the following corrections: dose levodopa in
sustained release form ? 0.75; dose of levodopa taken with
catechol-O-methyltransferase inhibitor ? 1.3. None of the 3
participants reported here took a dopamine agonist or mono-
amine oxidase inhibitor at the time of the evaluation.
Severity of dementia was staged according to the Clinical
Dementia Rating (CDR).15Impairment of function in 6 do-
mains (memory, orientation, judgment and problem solving,
community affairs, home and hobby, and personal care) is rated
on a 0–3 scale (0 ? normal; 1 ? mild; 2 ? moderate; 3 ?
severe). Global (weighted average) and sum CDR ratings are
presented. Other standardized assessments included Mini-
Mental State Examination (MMSE16), Neuropsychiatric Inven-
tory Questionnaire (NPI-Q17), and Mayo Fluctuations scale.18
In vivo amyloid imaging. [11C]-PIB was synthesized accord-
ing to published methods.19PET imaging was performed using a
Siemens 961 HR ECAT PET scanner (CTI, Knoxville, TN).
Approximately 12 mCi of radiotracer (range, 10.4–14.5; specific
activity ?1,200 Ci/mmol) was injected via an antecubital vein,
and a 60-minute, 3-dimensional (septa retracted) dynamic PET
scan was collected. Images were reconstructed as 5-minute
frames using scatter correction and a ramp filter. Frames were
corrected for head motion using in-house software, and coregis-
Table 1Clinical data
(ON)H-Y stageLEDD, mgMMSE
195 3521,115 2417 204
UPDRS3 ? Unified Parkinson’s Disease Rating Scale (motor subscale, maximum 108) during ON medication state; H-Y ?
Hoehn and Yahr stage; LEDD ? levodopa equivalent daily dose; MMSE ? Mini-Mental State Examination score (maximum
score 30); CDR Global ? Clinical Dementia Rating global score (0 ? cognitively normal; 0.5 ? very mild dementia; 1 ? mild
dementia; 2 ? moderate dementia; 3 ? severe dementia); CDR Sum ? sum of individual ratings for 6 domains of cognitive
function (maximum score 18); NPI-Q ? Neuropsychiatric inventory questionnaire (maximum score 39); Mayo Fluct. ? Mayo
fluctuations score (maximum score 4).
Neurology 74 January 5, 2010
tered to the patient’s T1-weighted magnetization-prepared rapid
gradient echo magnetic resonance scan obtained the same day.
For visual display, the data from 30 to 60 minutes after radio-
tracer injection were summed, Gaussian filtered (full width half-
maximum ? 6 mm), and normalized to average brainstem
For quantitative analyses, 3-dimensional regions of interest
(prefrontal cortex, gyrus rectus, lateral temporal cortex, precu-
neus, occipital lobe, caudate nucleus, brainstem, and cerebellum)
were created for each subject based on their individual MRI
scans, with boundaries defined as previously described.20Time-
activity curves were analyzed using Logan graphical analysis,
with the cerebellum (which has minimal specific binding due to
low A? plaque content) as the reference tissue input function.20,21
Binding potentials (BP) were calculated from the tracer distribu-
tion volume (DV, reflected in the slope of the Logan graphical
analysis) as BP ? DV ? 1. Mean cortical binding potentials
were calculated for each subject as the average of all cortical
regions except occipital lobe (which typically has lower A?
plaque burden, even in advanced AD). For comparison, pub-
lished mean values of MCBP calculated using identical methods
are 0.63 in DAT and 0.09 in age-matched controls20; values
greater than 0.2 are associated with low CSF A?42levels22and
are considered abnormally elevated.
Neuropathology. Brains were fixed in 10% neutral buffered
formalin for 2 weeks, paraffin wax-embedded, and sections cut at
6 ?m. Blocks were taken from frontal, temporal, parietal, and
occipital lobes, thalamus, striatum including the nucleus basalis
of Meynert, amygdala, hippocampus, midbrain, pons, medulla
oblongata, and the cervical spinal cord. Histologic stains in-
cluded hematoxylin and eosin and modified Bielschowsky silver
impregnation. Immunohistochemistry was performed using the
following antibodies: A? (10D5, Elan Pharmaceuticals, San
Francisco, CA), phosphorylated tau (PHF-1, supplied by Dr.
Peter Davies, Albert Einstein Medical School, Bronx, NY), ubiq-
uitin (Dako, Glostrup, Denmark), ?-synuclein (LB-509,
Zymed, CA), and TDP-43 (Proteintech, Inc., Chicago, IL).
Amyloid and tau burden was scored semiquantitatively in each
of the sampled regions (0 ? none; 1 ? few/mild; 2 ? moderate;
3 ? severe); ?-synucleinopathy with Lewy bodies was rated ac-
cording to the scheme proposed by McKeith et al.14where 0 ?
none; 1 ? ?1 Lewy body per ? 10 microscopic field; 2 ? 1–3
Lewy bodies; 3 ? 4–10 Lewy bodies; and 4 ? ?10 or numerous
RESULTS In vivo amyloid imaging. Images repre-
senting the distribution of [11C]-PIB PET activity
from 30 to 60 minutes after tracer injection are
shown in figure 1. Images from a 77-year-old female
control participant without neurologic disease are
displayed for comparison. Visual inspection revealed
high signal in multiple cortical areas for 2 patients
(case 1 and case 2), with relative sparing of primary
sensorimotor and visual cortex. This pattern was
highly similar to that previously described for pa-
tients clinically diagnosed with DAT.8,22,23In con-
trast, case 3 and the control participant showed
uptake predominantly in white matter regions. This
likely reflects nonspecific retention, as a recent study
showed that PIB binding to white matter homoge-
nates is nonsaturable.24
Binding potentials for selected regions of interest
and mean cortical binding potentials for the 3 indi-
viduals are presented in table 2. Cases 1 and 2 had
elevated PIB binding potentials in multiple cortical
regions, with relative sparing of the occipital cortex.
Case 1 also had elevated binding in the caudate nu-
cleus. In contrast, case 3 had binding potentials near
zero for all regions.
Neuropathology. Macroscopic findings included
mild frontal, temporal, and parietal atrophy and dila-
tation of the lateral ventricles (less in case 3 than in
cases 1 and 2), and normal hippocampal size in all 3
cases. As expected, there was pronounced loss of pig-
ment in the substantia nigra (see representative im-
ages in figure e-1 on the Neurology®Web site at
Histologic findings for case 2 are illustrated in
figure 2. In the substantia nigra, there was neuronal
loss, extracellular pigment, gliosis, Lewy bodies, and
Lewy neurites (figure 2, B and C). The parahip-
pocampal gyrus contained abundant Lewy bodies
(figure 2D) and moderate neurofibrillary tangle pa-
thology (figure 2G). Extensive A? deposits in the
frontal lobe were evident by immunohistochemistry
(figure 2A); there was also cerebral amyloid angiopa-
thy in leptomeningeal vessels.
Regional semiquantitative assessments of A?, tau,
and ?-synuclein burden for the 3 cases are presented
in table 3. All 3 cases had abundant Lewy bodies in
multiple neocortical and limbic regions. Cases 1 and
2 also had a high burden of A? plaque pathology
(Braak amyloid stage C25), predominantly in the
form of diffuse plaques. Although a few isocortical
neurofibrillary tangles were seen in these 2 cases, they
were very sparse and thus overall neurofibrillary tan-
gle burden was rated as limbic stage (Braak NFT
stage III26). In contrast, case 3 had minimal A?
plaques (Braak amyloid stage A), and only sparse
transentorhinal and entorhinal neurofibrillary tan-
gles (Braak NFT stage I). Cerebral amyloid angiopa-
thy was mild in case 1 and absent in the other 2 cases.
Modest vascular pathology in the form of arteriolo-
sclerosis was also a feature of all 3 brains (not shown).
There were no infarcts in any of the 3 cases.
The presence of Lewy bodies in brainstem, lim-
bic, and neocortical areas was consistent with PD
stage 6 (range: 0–6) in all 3 cases.27The density and
distribution of these lesions was also sufficient to
meet “high probability” criteria for dementia with
Lewy bodies14; because the parkinsonism preceded
the cognitive changes by more than 1 year, the entity
which describes these clinicopathologic features is
called PDD rather than DLB.1In cases 1 and 2, the
numerous neocortical A? plaques were sufficient for
neuropathologic diagnosis of AD by Khachaturian
Neurology 74January 5, 2010
criteria,28but the modest numbers of neuritic
plaques and neocortical tangles were only sufficient
to fulfill the criteria for “possible” AD according to
Consortium to Establish a Registry for Alzheimer’s
Disease criteria,29and there was only a “low likeli-
hood” that the cognitive changes are caused by AD
according to the NIA-Reagan Institute criteria.30No
other neurodegenerative diseases were identified in
any of the three cases.
DISCUSSION The absence of elevated cortical
[11C]-PIB binding in an individual with PDD who
had abundant cortical Lewy bodies and minimal cor-
tical amyloid plaque pathology underscores the spec-
ificity of this tracer for fibrillar A? amyloid in in vivo
imaging. Previous in vitro studies have demonstrated
that PIB does not demonstrate specific binding to
Lewy bodies (an amyloid composed of fibrillar
?-synuclein31) in cortex homogenates from patients
with Lewy body dementia lacking A? plaque, or to
synthetic ?-synuclein aggregates.32Our postmortem
evaluation of individuals who underwent amyloid
imaging strongly supports the notion that PIB PET
is specific for A? amyloid plaque pathology in vivo in
patients with Lewy body disorders. The burden of
cortical Lewy bodies in case 3 was comparable to that
Figure 1[11C]-PIB PET images
(A) Case 1. (B) Case 2. Increased signal is evident in multiple cortical areas in these 2 individuals, including orbitofrontal and
prefrontal cortex, precuneus, and temporal lobes. (C) Case 3. (D) Control participant. These 2 individuals have minimal PIB
signal in cortical areas. PIB retention in white matter areas is likely due to nonspecific binding (see text).
Table 2 Regional and mean cortical binding
potentials (unitless ratio)a
Case 1 Case 2Case 3
Prefrontal cortex (A)
Temporal cortex (B)
Occipital cortex (C)
Caudate nucleus (D)
Mean cortical binding
aLetters in parentheses are provided for cross-referencing
to the corresponding regions sampled for histopathologic
evaluation (see table 3).
Neurology 74 January 5, 2010
in the other 2 cases, yet cortical retention of PIB was
not elevated in this individual. Only the 2 cases with
high levels of cortical A? detected by immunohisto-
chemistry had elevated cortical retention of PIB on
in vivo imaging. Our methodology did not permit
detailed quantitative correlations between regional
PIB uptake and A? lesion burden on histopathology,
as previously reported for a case of AD.23Nonethe-
less, all measured cortical regions with an elevated
PIB binding potential (?0.2) in our study had severe
(grade 3) A? plaque burden.
An unexpected finding in our study was that the 2
PIB-positive PDD cases had low probability AD by
NIA-Reagan criteria. Evolving criteria for neuro-
pathologic diagnosis of AD account for some of the
conflicting results regarding the role of AD pathol-
ogy in the pathogenesis of PDD.1,33Consortium to
Establish a Registry for Alzheimer’s Disease and
NIA-Reagan criteria emphasize neuritic rather than
diffuse A? plaques as the major correlate of dementia
in AD. However, diffuse plaques may be the pre-
dominant pathology in the earliest, mild stages of
AD, and may indicate preclinical AD in cognitively
normal individuals.20,34The PIB-positive individuals
in this study had more advanced dementia (CDR
stage 2), a stage at which neuritic plaques are nearly
universally present in patients with DAT.35Thus in
the setting of PD, [11C]-PIB PET may have insuffi-
cient specificity for antemortem diagnosis of comor-
bid AD due to the inability to distinguish between
diffuse and neuritic A? plaques.
Since Lewy body pathology was advanced in all
cases, regardless of A? burden, ?-synucleinopathy
was likely central to the pathogenesis of PDD in
these individuals. However, since A? and ?-synuclein
pathologies may interact synergistically,36it is possible
that the presence of diffuse A? plaque influences the
evolution of dementia in individuals with PD, even
in the absence of neurofibrillary tangle pathology in-
dicative of comorbid AD. Diffuse A? plaques are
typically abundant in cases with cortical Lewy bod-
ies37,38and Lewy body counts are highly correlated
with amyloid plaque counts in PD and PDD.33,39
However, the timing of deposition of amyloid, Lewy
bodies, and neurofibrillary tangles relative to clinical
manifestations of dementia can only be inferred from
postmortem studies. Serial imaging to measure the
rate of amyloid deposition40in individuals with and
without Lewy body disorders (subsequently con-
firmed by autopsy) can directly test whether
?-synucleinopathy exacerbates amyloidosis and ac-
celerates cognitive decline.5Likewise, prospective
longitudinal follow-up of PIB-positive and PIB-
negative individuals with PD will be valuable for
ascertaining whether comorbid A? pathology influ-
Figure 2Postmortem examination, microscopic (case 2)
(A) A? (10D5) immunohistochemistry. Low-power micrograph shows extensive A? deposits in
the frontal lobe; there is also cerebral amyloid angiopathy in some leptomeningeal vessels. (B)
Hematoxylin and eosin. In the substantia nigra, there is neuronal loss, extracellular pigment,
gliosis, and a Lewy body (arrow) in a surviving pigmented neuron. (C–F) ?-synuclein (LB-509)
immunohistochemistry. (C) Lewy bodies and a Lewy neurite in the substantia nigra are more
readily seen by ?-synuclein immunohistochemistry. (D) Lewy bodies are present in the parahip-
pocampal gyrus. (E) Lewy bodies are present in subfield CA4 of the hippocampus. (F) Dystro-
(PHF-1) immunohistochemistry. Neurofibrillary tangles and neuropil threads are present in the
Neurology 74 January 5, 2010
ences the timing of onset, rate of progression, or
spectrum of clinical manifestations in PDD. This in-
formation will be crucial for developing targeted
therapies that can slow or prevent the onset of de-
mentia in patients with PD.
The authors thank the clinical, radiology, pathology, and technical staff
for making information and tissue samples available for this study and the
families of patients for participation. The authors thank the members of
the Alzheimer Disease Research Center at Washington University for help
with training in Clinical Dementia Rating.
This study was funded by NIH grants P01-AG03991, P50-AG05681,
U01-AG16976, K01-HD048437, R01-S041509, 5 T32-N2007205,
UL1 RR024992 (Clinical Science Translational Award at Washington
University), P30NS05710 (Neuroscience Blueprint Grant at Washington
University), American Parkinson Disease Association (APDA) Center for
Advanced PD Research at Washington University; Greater St. Louis
Chapter of the APDA; and the Barnes-Jewish Hospital Foundation (the
Elliot H. Stein Family Fund and the Jack Buck Fund for PD Research).
Dr. Burack receives salary and research support from the American Acad-
emy of Neurology (Clinical Research Training Fellowship), Medtronic,
Inc. (training fellowship), and foundation grants through the University
of Rochester; and during the study enrollment period her spouse held
stock in Amgen, Medtronic, Inc., Novartis, Pfizer Inc., Wyeth, and Astra-
Zeneca. J. Hartlein and H.P. Flores report no disclosures. L. Taylor-
Reinwald receives research support as study coordinator/research assistant
from the NIH/NIA [P01-AG03991 and P50-AG05681]. Dr. Perlmutter
serves on scientific advisory boards for the American Parkinson Disease
Association and the Dystonia Medical Research Foundation; serves on the
editorial boards of Neurology®; has received honoraria from Ceregene, the
Parkinson Disease Study Group (grant reviews), the NIH (review activi-
ties), and for speaking and educational activities not sponsored by indus-
try; and has received/receives research support from Medtronic, Inc.
(partial fellowship support), the NIH [RO1 1RO1NS41509 (PI), RO1
NS050425 (PI), RO1 NS058714 (PI), P30 NS057105 (Co-I Core B),
NCRR RR024992 (Project PI), R01ES013743 (Co-I), R01 NS039821
(Co-I), R01NS058797 (Co-I), and CO6 RR020092 (Program Direc-
tor)], the Huntington Disease Society of America, HiQ Foundation,
Bander Medical Business Ethics Foundation at Washington University,
McDonnell Center for Higher Brain Function, the Michael J. Fox Foun-
dation, Greater St. Louis Chapter of the American Parkinson Disease
Association, American Parkinson Disease Association, APDA Advanced
PD Research Center at Washington University, and the Barnes-Jewish
Hospital Foundation. Dr. Cairns serves on the editorial boards of Acta
Neuropathologica and Brain Pathology and receives research support from
Table 3 Regional molecular pathologya
Case 1 Case 2Case 3
DPCP CAANFTNPLBDP CPCAANFTNP LBDP CPCAANFTNP LB
Middle frontal gyrus (A)
Inferior parietal lobule
Occipital lobe (C)
Nucleus basalis of
CAA ? cerebral amyloid angiopathy; CP ? cored plaque; DP ? diffuse plaque; LB ? Lewy body; NFT ? neurofibrillary tangle;
NP ? neuritic plaque; PIB ? Pittsburgh Compound B; 0 ? none; 1 ? few/mild; 2 ? moderate; 3 ? severe; 4 (Lewy bodies
only) ? numerous/very severe.
aLetters in parentheses are provided for a subset of regions to facilitate cross-referencing to the corresponding PIB-PET
imaging data presented in table 2.
Neurology 74 January 5, 2010
the NIH [P01-AG03991 (Neuropathology Core PI) and P50-AG05681
(Neuropathology Core PI)], and the Charles and Joanne Knight Alzhei-
mer Research Initiative.
Received June 18, 2009. Accepted in final form October 12, 2009.
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Start Planning Your Trip to the 62ndAAN Annual
Meeting in Canada Today!
What You Need to Know to Get You There
Now is the time to start planning your trip to Canada—and if you are a visitor, it is important that
you know about valid travel documentation requirements and proof of citizenship. Here are some
important things to keep in mind when planning your trip:
● Document requirements vary depending from which country you are traveling, the reason for
your visit, the length of your stay
● Special no-fee passports may be required for US federal government employees
● The US Department of State now offers expedited passport service for US residents
For additional information on traveling to Canada, including tips on customs and immigration,
currency, health insurance, luggage requirements, and mobile phone service, visit www.aan.com/
Neurology 74January 5, 2010