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An Overview of PET Neuroimaging

Ilya Nasrallah, MD, PhD, and Jacob Dubroff, MD, PhD


Over the past 35 years or so, PET brain imaging has allowed powerful and unique insights into
brain function under normal conditions and in disease states. Initially, as PET instrumentation
continued to develop, studies were focused on brain perfusion and glucose metabolism. This
permitted renement of brain imaging for important, nononcologic clinical indications. The
ability of PET to not only provide spatial localization of metabolic changes but also to accurately
and consistently quantify their distribution proved valuable for applications in the clinical
setting. Specically, glucose metabolism brain imaging using (F-18) uorodeoxyglucose
continues to be invaluable for evaluating patients with intractable seizures for identifying
seizure foci and operative planning. Cerebral glucose metabolism also contributes to
diagnosis of neurodegenerative diseases that cause dementia. Alzheimer disease, dementia
with Lewy bodies, and the several variants of frontotemporal lobar degeneration have differing
typical patterns of hypometabolism. In Alzheimer disease, hypometabolism has furthermore
been associated with poorer cognitive performance and ensuing cognitive and functional
decline. As the eld of radiochemistry evolved, novel radioligands including radiolabeled
umazenil, dopamine transporter ligands, nicotine receptor ligands, and others have allowed
for further understanding of molecular changes in the brain associated with various diseases.
Recently, PET brain imaging reached another milestone with the approval of (F-18) orbetapir
imaging by the United States Federal Drug Administration for detection of amyloid plaque
accumulation in brain, the major histopathologic hallmark of Alzheimer disease, and efforts
have been made to dene the clinical role of this imaging agent in the setting of the currently
limited treatment options. Hopefully, this represents the rst of many new radiopharmaceuticals that would allow improved diagnostic and prognostic information in these and other
clinical applications, including Parkinson disease and traumatic brain injury.
Semin Nucl Med 43:449-461 C 2013 Elsevier Inc. All rights reserved.

everal tomographic imaging modalities, including CT and


MRI, were rapidly evolving in the mid-1970s allowing for
noninvasive structural visualization of the living human brain as
never before.1-4 During this time, PET also reached this incredible milestone.5 PET was able to demonstrate an in vivo spatial
pattern of brain activation as a direct result of its ongoing metabolism and not its water content or density as in the case of MRI
and CT, respectively. The coupling of blood ow and metabolism to underlying variations in cellular ionic products that
occurs in normal brain function had long been formulated and
attributed to Roy and Sherrington6 who later were awarded the
Nobel Prize in Physiology and Medicine for this contribution.7
Division of Nuclear Medicine and Clinical Molecular Imaging, Department of
Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA.
Address reprint requests to Jacob Dubroff, MD, PhD, Department of
Radiology, Division of Nuclear Medicine and Clinical Molecular Imaging,
Hospital of the University of Pennsylvania, 3400 Spruce Street, 110
Donner, Philadelphia, PA 19104. E-mail: jacob.dubroff@uphs.upenn.edu

0001-2998/12/$-see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.semnuclmed.2013.06.003

Brain PET: An Abridged History


Perfusion and Metabolism
Initially, as emission tomography instrumentation was rapidly
evolving, application of PET in the brain focused on perfusion
and metabolism. (C-11) CO, (N-13) NH3, and (O-15) water
were the most commonly used radiopharmaceuticals and
provided novel insights into brain blood ow and oxygen
consumption at baseline and other states. For example, with
this newly discovered ability to demonstrate blood ow and
oxygen supply changes in brain, there was growing evidence
that PET could play a prominent role in the diagnosis and
management of stroke and cerebrovascular disease.8,9 However, because of the intrinsic challenges of radiopharmaceutical
production, especially relative to the rapidly evolving time
course of cerebral ischemia, PET mapping of oxygen supply
and perfusion failed to build momentum to establish itself in
the routine clinical workow.
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I. Nasrallah and J. Dubroff

450

In Vivo Brain Mapping


Concomitantly, there was signicant momentum building in
visualizing glucose metabolism, recognized as the primary fuel
of the central nervous system, through autoradiography. Louis
Sokoloff helped to pioneer this effort10 using it most dramatically to show the plastic ocular dominance maps that launched
Torsten Wiesel and David Hubel11,12 to their shared Nobel
Prize. Rather than having to record electric responses from
individual neurons and painstakingly render a topographic map
of brain function, Sokoloff showed how thousands of neurons
would change their behavior in a pattern offering a broader path
into studying systems neuroscience.10,13 Along the same lines,
Marcus Raichle et al.14 at Washington University used (C-11)
glucose to examine brain glucose utilization in rhesus monkeys.
Application in the clinic became possible with the substitution of
F-18 and its 110-minute half-life by Tatsuo Ido and Al Wolf at
Brookhaven National Laboratory15 in a collaboration with the
University of Pennsylvania. (F-18) Fluorodeoxyglucose (FDG)
was soon applied to in vivo glucose mapping in humans.5

Intrinsic Physiological Variability


In the studies that followed, the regional brain glucose
metabolism in a number of normal physiological settings was
explored. For example, Greenberg et al.16 examined changes in
FDG brain distribution that occurred in primary sensory
cortices including in response to visual, somatosensory, and
auditory stimulation; Phelps et al.17 also showed difference in
glucose metabolism in primary visual cortex related to visual
stimulation and deprivation. Chugani and Phelps18 demonstrated changes in brain glucose metabolism that occur during
normal development. Kuhl et al.19 used FDG-PET to reveal the
decline in brain glucose metabolism that occurs with normal
aging. Gur et al.20 even showed intrinsic differences in the
regional brain glucose metabolism between men and women.
Despite these nuances of intrinsic variability, a normal pattern
of brain (F-18) FDG uptake is recognized and serves as the
basis for qualitative clinical interpretation (Fig. 1).

Quantication Strategies
One of the strengths of PET brain imaging lies in the ability
to accurately quantify radiotracer distribution in brain.

Mathematical prowess, astute modeling, and comprehensive


understanding of the underlying biology were required to
achieve this capacity. To gain many of the aforementioned
insights into glucose metabolism, Sokoloff et al.21 thoroughly
described the process in rats using autoradiography, which
was then reproduced using PET in humans.5,22,23 In turn,
Patlak et al.24 developed a graphical analysis technique using
linear regression for modeling the irreversible binding of a
radioligand on a receptor as in the case of (F-18) FDG.
Mintun et al.25 coined the term Binding Potential in their
1984 Annals of Neurology manuscript to reect a brain
regions total ability to interact with a radioligand as they
concluded that the relationship between the number of
receptor binding sites (Bmax) and a given radioligands binding
afnity for a given receptor were inseparable. This was an
important advancement in PET brain imaging as it could be
applied to different radiopharmaceuticals and did not assume
irreversible binding of the radioligand to the receptor. Jean
Logan built on Patlaks tactic and conceived a graphical analysis
technique using linear regression to model reversible radioligand binding on receptor that is widely used to date.26-28 A
consensus for the terminology used in the compartmental
modeling of reversible binding radioligands was published in
2007 in the Journal of Cerebral Blood Flow of Metabolism.29

Epilepsy
Background and Potential Effect
Epilepsy, the predisposition to recurrent, unprovoked
seizures,30 is estimated to affect approximately 1% of the
population and 3% at some point in their lives.30-32 Approximately 30% of these patients have intractable epilepsy because
pharmacologic therapy is insufcient to reduce seizure frequency.32,33 Clinical interventions for drug-resistant epilepsy,
including intracranial stimulation, vagal nerve stimulation, and
surgical resection of brain, have been proven to have various
degrees of efcacy at achieving seizure relief.34,35 Surgical brain
resection, in the appropriate clinical context, is the most widely
accepted treatment for intractable epilepsy. However, epilepsy
is not a homogeneous condition, rather it consists of a
spectrum of syndromes, etiologies, and seizure types.36,37

Figure 1 Normal uorodeoxyglucose (18-F) brain uptake seen in the transaxial (A), sagittal (B), and coronal (C) planes.
Note the most intense uptake is present in the striatum followed closely by the thalami and occipital cortex (transaxial
view). FDG distribution is evenly distributed throughout the remaining cortices, slightly decreased in the temporal lobes
(coronal and sagittal views).

PET brain imaging


Hence, thorough evaluation by a qualied epileptologist
should drive the need for imaging.
It is estimated that half of those patients with intractable
epilepsy are well-suited surgical candidates. However, despite
an estimated 100,000 epileptics thought to be good candidates
for surgical resection in the United States annually, only
approximately 2000 undergo surgery.32 In 2008, Choi
et al.38 published a decision analysis paper on postsurgical
epilepsy outcomes in Journal of American Medical Association
using a Monte Carlo simulation that further underscores this
issue. They found that for a 35-year-old patient with anterior
temporal lobe epilepsy who underwent surgical resection,
compared to remaining on pharmacotherapy, life expectancy
would increase by 5 years, with a 7.5-year increase in qualityadjusted life expectancy.38 Baxendale et al.39 even found
signicant increases in visual and verbal learning in epileptic
patients who underwent unilateral anterior temporal lobe
resections. However, surgery is not without risks and some
patients do not achieve seizure relief.35,40 Additionally, in the
patients who do experience signicant benet from surgery
(decrease in seizure activity), there is a signicant reduction in
their healthcare costs compared with before surgery and to
those patients who do not achieve a clinical benet.41,42
Therefore, there is a great deal at stake for both improving
the lives of a signicant number of patients and our ability to
control the growth of healthcare costs.

Ictal vs Interictal Imaging


Using PET imaging, it became evident from early on that
different patterns of brain glucose metabolism were present in
patients in epilepsy as seen by (F-18) FDG imaging.43-45
Studying 17 patients with partial epilepsy, Kuhl et al.43
importantly observed that interictal temporal lobe hypometabolism was often spatially concordant with electroencephalogram (EEG) abnormalities. Engel et al.46-48 further
rened their observations of brain hypometabolism in the
context of EEG and postsurgical pathology. They also found
that ictal (F-18) FDG imaging revealed unexpected locations of
hypermetabolism; specically ones not usually implicated in
experimental models of epilepsy.49 Combining these observations in the context of a battery of other neurologic testing
including EEG and neuropsychological testing has evolved
into the standard for patients with epilepsy being considered
for surgical resection. Pairing of ictal and interictal single
photon emission computed tomography (SPECT) brain perfusion imaging is a technique some epilepsy centers utilize to
localize epileptogenic foci; however, this is logistically challenging.50 Best practice requires injection timing of a Tc99mlabeled hexamethylpropyleneamine oxime (HMPAO) or ethyl
cysteinate dimer (ECD) just after seizure onset followed by
timely SPECT brain imaging; therefore, a healthcare professional trained both to recognize seizure onset and in radiation
safety who can administer radiopharmaceuticals must remain
with the patient in the epilepsy monitor unit for extended
periods of time.50 Because of the limited 110-minute half-life of
(F-18) and the longer uptake time for FDG, which may
continue to accumulate in propagating brain seizure activity,

451
ictal (F-18) FDG-PET imaging remains impractical in the
clinical setting.

Outcomes
The goal for surgical resection is complete seizure freedom.
Engel developed a classication scale for postoperative outcomes: class I (free of disabling seizures), class II (rare disabling
seizures), class III (worthwhile improvement), and class IV (not
worthwhile improvement).32,51 This ordinal scale is often used
for determining postoperative seizure control.52 The other
prominent postoperative classication is the 6-point scale
developed by the International League Against Epilepsy.53 In
classic mesial temporal lobe epilepsy, ndings of hippocampal
atrophy and ipsilateral temporal lobe hypometabolism are
present. A representative case of mesial temporal sclerosis
associated with epilepsy is shown in Figure 2. However, there
is building evidence that even in the absence of a morphologic
lesion seen on MRI, patients with temporal lobe hypometabolism that is concordant with EEG abnormalities or seizure
semiology or both may have signicant freedom from seizures
after temporal lobe resection.54-57 However, there remains
signicant information to be gained using MRI.58,59 As a
spatially rigid structure, the brain lends itself well to coregistration between imaging modalities. Specically, several studies
have examined the potential of MRI and (F-18) FDG-PET
coregistration.57,60,61 The two57,61 techniques found signicant benet of coregistration for detection of hypometabolic
foci in patients with focal cortical dysplasias, a signicant cause
of epilepsy in which neurons fail to migrate appropriately
during brain development.62

Quantication of (F-18) FDG in Epilepsy


Because (F-18) FDG-PET interictal brain imaging can be
performed in a fairly reproducible fashion and Patlak modeling
provides a reliable quantication technique, multiple studies
have examined the relationship between abnormal FDG brain
quantication patterns with clinical characteristics. The duration of frontal and temporal lobe epilepsy was associated with
the degree of hypometabolism in the ipsilateral hippocampus
and thalamus.63 In turn, the degree of metabolism asymmetry
has been linked with seizure freedom after resection, with a
greater degree of asymmetry associated with poorer patient
outcomes.64,65 Merely the presence of thalamic asymmetric
hypometabolism has been associated with a decreased success
rate in seizure freedom in patients with refractory temporal
lobe seizures who underwent temporal lobectomy.66 As
patient follow-up after an intervention remains challenging,
there are few studies that follow patients with intractable
epilepsy before and after surgery. However, in one study of 28
patients with intractable epilepsy who underwent temporal
lobe resection and achieved complete seizure freedom, quantitative comparison of preoperative and postoperative (F-18)
FDG-PET brain imaging revealed reproducible changes in
brain regional glucose metabolism ipsilateral to the side of
temporal lobectomy, including increases in the anterior insula,
inferior precentral gyrus, anterior cingulate gyrus, and

I. Nasrallah and J. Dubroff

452

Figure 2 Representative transaxial FDG-PET and MRI FLAIR images from a 20-year-old female with intractable seizures. On
MRI, note the shrunken-appearing left hippocampus (B). The FDG-PET demonstrates hypometabolism throughout the left
temporal lobe (A).

supramarginal gyrus metabolism as well as decreases in the


caudate nucleus, pulvinar, fusiform gyrus, lingual gyrus, and
posterior insula metabolism.67 No changes in metabolism
contralateral to the side of brain resection were identied.67

Nonglucose PET Imaging of Epilepsy


Although the incorporation of (F-18) FDG-PET imaging has
become a mainstay in evaluation of patients with intractable
epilepsy, abnormalities in regional brain glycolysis represents
only one method of identifying brain activity. Gammaaminobutyric acid (GABAergic) modulation of inhibitory
neurotransmission is critical for neuronal reorganization under
a number of conditions and has been implicated in the
pathogenesis and treatment of epilepsy.68-77 PET brain imaging using both C-11 and F-18 formulations of umazenil, a
GABA-A receptor antagonist, has shown that depressed
inhibitory neurotransmission often drives seizure propagation.68,78-85 Although umazenil binding slightly decreases
during normal brain development,86 treatment of childhood
epilepsy with vigabatrin, an antiepileptic drug that inhibits
GABA breakdown, further decreases GABA-A receptor expression.79 Focally depressed GABA-A receptor expression has
been demonstrated with several types of neocortical lesional
epilepsy in which surgical removal of the lesion in question
often results in seizure freedom.78,81,84 Diffusely decreased
umazenil binding has been observed in the autosomal
recessive enzyme deciency of succinic semialdehyde dehydrogenase, known to cause epilepsy,68 as well as in hippocampus and temporal lobe ipsilateral to seizure onset in
intractable temporal lobe epilepsy.80
Dysfunction of serotonergic, dopaminergic, and mu opioid
signaling has also been implicated in seizure disorders and
studied with PET.87-93 Depressed dopamine uptake in the
striatum has also been observed in patients with temporal lobe
epilepsy.94-96 Both dopaminergic and nicotinic receptor abnormalities have been observed in autosomal dominant nocturnal
frontal lobe epilepsy, known to have alpha and beta nicotinic
receptor subunit abnormalities.96,97 Decreased serotonin
receptor expression (5HT-1) in the temporal lobe ipsilateral

to seizure onsent using the radioligand (F-18)-(N-[2-{4-(2methoxyphenyl) piperazino}]-N-[2-pyridinyl]trans-4-uorocyclohexanecarboxamide) (FCWAY) has been demonstrated
in several studies.89-91,98-100 This asymmetry has been
observed to be more prominent than hypometabolism seen
with (F-18) FDG-PET,90 and, in turn, it has been suggested
that PET serotonin receptor mapping may have signicant
benet for surgical planning91 for patients with intractable
temporal lobe epilepsy. Because tryptophan, an essential
amino acid, is critical for serotonin synthesis, (C-11)-labeled
tryptophan has been used as a surrogate marker to study
epilepsy.101-108 Interestingly, increased tryptophan metabolism was observed in temporal cortex ipsilateral to seizure
onset,108 and tryptophan metabolism increased in the lentiform nucleus ipsilateral to side of seizure onset after temporal
lobe resection.102 Focal increases in amino acid metabolism
have been postulated to occur in epileptogenic neocortical
lesions such as focal cortical dysplasias and tuberous sclerosis;
there is evidence that (C-11) tryptophan PET imaging can
identify these lesions better than MRI or (F-18) FDG-PET
imaging.101,103-105,107 (C-11)-labeled methionine, another
essential amino acid, has also been shown to be focally
increased in focal cortical dysplasia.109,110
Intractable epilepsy represents a challenging disease to treat
as the underlying neuronal changes that result in successful
outcomes remain uncertain.67,111,112 Despite treatment improvements, some patients do not achieve seizure relief.35,40
Improved understanding of changes occurring during both
successful and unsuccessful therapy would enhance clinical
decision making and improve understanding of adult neuronal
reorganization as well as potentially suggest novel treatment
strategies. PET brain imaging, using traditional (18-F) FDG as
well as novel radiopharmaceuticals, is well poised to drive this
process.

Dementia
Dementia is dened as a decline of cognitive or neuropsychological function not explained by other psychiatric disorder
that interferes with usual activities. Cognitive and behavioral

PET brain imaging


decline must be seen in at least 2 domains: memory, reasoning
or judgment, visuospatial abilities, language, or behavior.
There are numerous causes of dementia, with Alzheimer
dementia (AD) being the most common. Other etiologies
include dementia with Lewy bodies (DLB), frontotemporal
lobar degeneration (FTLD), vascular dementia, and structural
causes including normal pressure hydrocephalus.
Although diagnosis of the underlying pathophysiology of
advanced disease is often possible on clinical grounds alone,
early diagnosis can be more challenging. Improved or earlier
diagnosis can help with prognosis and potentially the selection
of the most appropriate disease-modifying treatment. FDGPET has the benet of being able to diagnose various neurodegenerative dementia syndromes of differing etiologies.
Furthermore, neurodegenerative dementias are unlikely in
the setting of a normal scan, with specicity of approximately
75%.113,114 PET studies have been shown to increase diagnostic certainty and often change clinical diagnoses in the
evaluation of dementia.115
There are multiple potential etiologies of regional decreased
FDG uptake in dementia. Neurodegenerative dementias are
associated with specic patterns of regional atrophy that match
the pattern of hypometabolism, and some studies suggest that
much of the hypometabolism in Alzheimer disease is due to
regional volume loss.116 Other factors that could contribute to
regional hypometabolism include disorders of glucose metabolism,117 decreased synaptic connectivity,118,119 and deafferentation.120

Alzheimer Dementia
AD is a progressive neurodegenerative disease with an insidious cognitive decline that is characterized by a combination of
inability to acquire new memories, impaired reasoning and
judgment, impaired visuospatial ability, impaired language
function, and changes in personality and behavior.121 AD
accounts for approximately 50%-60% of all causes of dementia. The incidence of AD increases with age.122 AD is
pathologically associated with accumulation of amyloid neuritic plaques and neurobrillary tangles containing the tau
protein.123 Recent estimates of the prevalence of AD in the
United States range from 2.4-4.5 million people124; numbers
projected to continue to increase as the population continues
to get older.
It has been recognized that the pathophysiological processes
that underlie AD commence years before patients can be
classied as demented; there is evidence that amyloid accumulation precedes the onset of clinical symptoms by many
years.125 Memory complaints, other milder cognitive decits,
and abnormalities on neurocognitive testing can be detected in
a group of nondemented patients who belong to this predementia phase of Alzheimer disease termed mild cognitive
impairment (MCI), years before the onset of dementia.126,127
The prevalence of MCI in the United States is approximately
5.2 million people.128 Patients with MCI have a greater rate of
cognitive decline129 and greater risk of progression to dementia
than patients with normal cognition,130 with conversion to AD
estimated between 5%-16% per year,131 but up to one-third

453
revert to normal cognition.132 Furthermore, efforts have been
made to identify cognitively normal patients with the earliest
pathophysiological changes characteristic of AD.133
On FDG-PET, AD demonstrates a characteristic temporal
and parietal hypometabolism with involvement of the medial
parietal lobe including the precuneus and the posterior
cingulate cortex (Fig. 3A). Temporoparietal hypometabolism
is the characteristic nding134 and is seen early in the disease
course, with more advanced cases also showing worsening
hypometabolism more broadly in the brain, particularly in the
frontal lobes.135 There is typically sparing of primary somatosensory cortex, visual cortex, the basal ganglia and thalami, and
the cerebellum. This pattern of hypometabolism may be
asymmetric but is usually bilateral.136,137
Numerous studies, both small and large, have evaluated the
performance of FDG-PET for the diagnosis of AD. Sensitivity
and specicity values have varied, but reasonable estimates
for the sensitivity is 78%-94% and for specicity is
63%-86%.113,114,134,138-140 Studies have shown that FDGPET provides useful information in the evaluation of a
demented patient. A study by LaForce et al.141 demonstrated
that in a cohort of patients with MCI and AD, the diagnoses of
29% of cases were changed based on FDG-PET, with FDGPET being most useful in atypical or uncertain etiologies of
dementia. FDG-PET has been shown to have modestly greater
sensitivity and specicity than initial clinical examination.139,141 Patients with amnestic MCI and patients
with MCI with multiple cognitive domains affected tend to
demonstrate an AD pattern, with the severity of hypometabolism less severe than in AD. MCI remains a heterogeneous
population owing to the difculty in establishing the
underlying pathophysiology, and many MCI cases demonstrate normal or other patterns of hypometabolism on FDGPET.135
FDG-PET studies can be used to derive prognostic information for patients with AD and MCI. Lower metabolism at
baseline was associated with poorer cognitive performance142
and subsequent cognitive and functional decline.137 Worsening of hypometabolism in AD and in MCI is associated with
progressive cognitive and functional decline.136,137,143 Furthermore, an AD pattern of hypometabolism in patients with
MCI is correlated with progression to AD.136,140 On the
contrary, a normal appearance on FDG-PET is strong evidence
that MCI is not due to an underlying neurodegenerative
condition.135

Dementia with Lewy Bodies


DLB is a progressive neurodegenerative dementia characterized by visual hallucinations, executive function disruption,
uctuation in attention, and extrapyramidal motor symptoms
or Parkinsonism such as bradykinesia and rigidity.144-146 Early
in the course of the disorder, there is sparing of memory
function. DLB is the etiology of approximately 10%-15% of
dementia.144
DLB is part of a spectrum of disorders of alpha-synuclein
that also includes Parkinson disease, which also demonstrates
neural Lewy body formation, and multisystem atrophy.144-146

I. Nasrallah and J. Dubroff

454

Figure 3 Typical FDG uptake patterns in neurodegenerative dementias. (A) Alzheimer dementia characteristically features
parietotemporal hypometabolism. (B) Dementia with Lewy bodies also demonstrates parietotemporal hypometabolism;
however, additional occipital hypometabolism is often present, a nding not characteristic for AD. (C) Frontal variant
frontotemporal dementia with classical frontal and temporal hypometabolism. (D) Progressive nonuent aphasia variant of
FTD with marked asymmetry, almost exclusively involving the left temporal and parietal lobes.

Typical age of onset ranges from 60-90 years.146 DLB is


distinguished from dementia caused by Parkinson disease
(termed Parkinson disease dementia) by onset of dementia
before or simultaneously with the onset of Parkinsonism. In
70% of cases, DLB is associated with Alzheimer-type pathology
that is characterized by amyloid plaque formation but few
neurobrillary tangles. In 30% of cases, DLB is not associated
with amyloid plaques.146
On FDG-PET, DLB is characterized by a posterior predominant, occipitoparietal hypometabolism, but can also be more
extensive (Fig. 3B).135 Occipital hypometabolism, which is rare
in AD, was shown to differentiate DLB from AD with sensitivity
of 90% and specicity of 80%.147

Frontotemporal Lobar Degeneration


FTLD is a group of dementia syndromes characterized by
behavior and personality changes, impairment of executive
function, and language abnormalities such as aphasia. There
are 3 clinical syndromes: behavioral or frontal variant frontotemporal dementia (FTD), which is the most common,
semantic dementia, and progressive nonuent aphasia. It is
most common in ages 45-65 years, which is a younger cohort
than typical for AD, although at these ages FTLD and AD have
similar prevalence overall.148,149
For FTD, the most typical pattern on FDG-PET consists of
predominately frontal hypometabolism (Fig. 3C), with varying
involvement of the anterior cingulate cortex and anterior
temporal lobes, seen with the behavioral or frontal variant.150
Some reports have demonstrated hypometabolism in the basal
ganglia in addition.151 Semantic dementia is associated with
predominately anterior temporal lobe hypometabolism that is
usually asymmetric,152 whereas progressive nonuent aphasia
is even more asymmetric (Fig. 3D), associated with left

perisylvian hypometabolism.151 These patterns match the


regional atrophy characteristic of FTD on structural imaging
and pathologic studies.149 Although usually distinguishable
from AD, FTD can present with hypometabolism patterns
typical of AD, including cases with only temporal hypometabolism and cases of temporoparietal hypometabolism, usually
but not always seen in conjunction with frontal hypometabolism.135,153 Involvement of the anterior cingulate and
anterior temporal lobes is more suggestive of FTD,153 whereas
FTD is less likely to involve the medial temporal lobes or
hippocampi than AD.135

Other Etiologies of Dementia


Many other etiologies of dementia have demonstrable structural or metabolic abnormalities, and as such can be evaluated
with MRI or with laboratory testing. Etiologies including
normal pressure hydrocephalus, extraaxial hemorrhage, or
intracranial mass are not reliably evaluated with PET. However,
in some of these conditions, there are suggestive features on
FDG-PET. Vascular dementia refers to a heterogeneous group
of disorders that can result in cognitive decline, including
territorial or lacunar infarcts, cerebral hemorrhage, leukoaraiosis, or hypoperfusional states. Approximately 5% of cognitive impairment in the elderly is caused by a vascular
etiology.154 Vascular dementia typically demonstrates asymmetric hypometabolism and often involves brain regions
spared in Alzheimer and other neurodegenerative dementias,
including primary somatosensory cortex and subcortical
structures such as the basal ganglia and thalami.155-157
Cognitive decline due to a combination of Alzheimer disease
and vascular factors is not uncommon.158 Correlation with
MRI can be helpful in evaluating for a vascular contribution to
cognitive decline.

PET brain imaging

Cerebral Amyloid Imaging


Although the pathogenesis of AD remains unknown, the
characteristic neuropathologic changes are accumulation of
amyloid plaque and tau-containing neurobrillary tangles,
with 96% of patients with AD demonstrating cerebral amyloid.132,159 There is evidence that this amyloid plaque accumulation even precedes the onset of dementia or any cognitive
symptom. Specic agents for visualizing amyloid plaque have
long been known to pathologists, and these have been adapted
to molecular imaging agents. The earliest agent to gain widespread use was the carbon-11 Pittsburgh compound B
(PiB),160 but subsequently uorinated compounds have been
generated, with one now approved for clinical use, (F-18)
orbetapir (Amyvid, previously AV-45). These agents bind to
brillar amyloid plaques, one form of plaque that accumulates in Alzheimer disease.161 PiB and orbetapir uptakes have
been shown to be highly correlated.162 PiB demonstrates
improved cortical retention compared with orbetapir,162
but has less widespread availability owing to the carbon-11
radiolabel. Florbetapir is approved for use as a binary
interpretation (Fig. 4); no to minimal cortical uptake is
correlated with no to sparse amyloid plaque and indicates a
negative scan, whereas cortical uptake in at least 2 brain regions
to the level of extensive cortical uptake is correlated with
moderate to severe amyloid plaque burden and indicates a
positive scan.163
Binding of amyloid agents has been shown to correlate with
the burden of amyloid plaque.160,164,165 Patients with AD have
higher levels of amyloid tracer uptake and higher rates of
increases in tracer uptake than patients with MCI, which have
higher levels and rates than cognitively normal controls.166,167
In the setting of a university memory clinic, a study using a
combination of FDG-PET and amyloid imaging with PiB
showed a change in 23% of diagnoses and increased diagnostic
condence, particularly in cases that were initially less
certain.115 Positive amyloid scans have been associated with
poorer memory performance in patients with MCI159; however, the level of cortical uptake of PiB was not shown to
directly correlate with performance on a cognitive test.142 It is
important to note that even cognitively normal patients also
demonstrate increasing amyloid plaque burden with aging,166

455
with approximately 22%-30% of cognitively normal patients
demonstrating detectable cortical amyloid tracer uptake.
Uptake in cognitively normal patients is typically low, and
usually discernible from AD.132,159,168
Although only recently available, the clinical use of amyloidimaging agents remains limited. The Society of Nuclear
Medicine and Molecular Imaging and the Alzheimers Association have proposed appropriateness criteria, identifying
3 indications where clinical amyloid imaging may be most
useful.169 First, testing may benet patients with persistent or
progressive but unexplained MCI. Second, patients who may
have AD but have an atypical or mixed course. Lastly, amyloid
imaging may prove benecial in patients with early onset but
progressive dementia.142 A further consideration is that
although recent phase 3 clinical trials of antiamyloid immunotherapy agents did not show improvement in cognitive
scores of patients with Alzheimer disease, it remains possible
that early treatment with these or similar agents may prove to
have disease-modifying effects.170 In this setting, amyloidimaging agents could be used to identify patients who may
benet from such intervention.
The consensus paper by Johnson et al. further identied
situations where amyloid imaging is inappropriate in the
clinical setting. Primarily, these involved cases where the
clinical diagnosis of AD is highly certain or for asymptomatic
patients. In these cases, treatment decisions and clinical outcomes are not likely to benet. Unlike FDG-PET, amyloid
imaging does not allow evaluation for pathologic conditions
not characterized by amyloid accumulation, such as FTLD.
Although there is some evidence that amyloid tracer uptake
has prognostic efcacy for evaluation of progression from MCI
to AD,140 it appears that FDG-PET provides better prognosis
for cognitive function. Recent data indicates that amyloid
agents can detect increasing amyloid plaque in patients with
normal cognition before clinical symptoms arise, even 15 years
before plateau levels of amyloid plaque,171 and there is some
suggestion that PiB uptake may correlate with mild impaired
memory performance in healthy controls.159 However, potential use in cognitively normal patients could lead to unnecessary stress, testing, and potentially harmful treatment in
patients who would never progress to develop signicant
cognitive symptoms.

Figure 4 (F-18) orbetapir PET transaxial images. (A) Negative scan: in a cognitively normal patient, there is low cortical
uptake with preservation of gray-white discrimination. (B) Positive scan, indicating moderate to severe amyloid neuritic
plaque, here in a patient with Alzheimer dementia. There is cortical tracer uptake, which is in this case diffuse.

I. Nasrallah and J. Dubroff

456

Figure 5 (F-18) uoropropyl-dihydrotetrabenazine (AV-133) PET transaxial images of the midbrain obtained in a healthy
control (A) and in a patient with Parkinson (B). Note the levels of VMAT2 are more depressed in the posterior aspect of the
striatum.

Emerging Indications
Parkinson Disease
Parkinson disease is a neurodegenerative disorder characterized
by loss of dopaminergic neurons in substantia nigra and the
striatum. It is the second most common neurodegenerative
disease after Alzheimer disease and thought to affect approximately 4.5 million worldwide, with that number estimated to
double by 2030.172 The clinical hallmark of Parkinsonian motor
symptoms includes tremor, rigidity, slowness of movement, and
postural instability.173 Although the SPECT tracer Ioupane has
recently become used in the United States to distinguish
Parkinsonian tremor from essential tremor, the cascade of events
leading to accumulation of the protein alpha-synuclein and
subsequent dopaminergic dysfunction remains unclear.174
Additionally, Ioupane has been successfully used in Europe
for dementia evaluation as patients with diffuse Lewy body
dementia have depressed levels of dopamine transporter; this
indication has not been approved in the United States.175,176
PET imaging of the brain using the radioligand (C-11)
tetrabenzine allowed for visualization of monoamine vesicular
transporter, a pathway fundamental for dopaminergic neurotransmission.177 Further evaluation led to the use of (C-11)
dihydrobenzine, which, as a VMAT2 marker, has been shown to
be very promising both as a biomarker for Parkinson disease178
and for dementia diagnosis.179 More appropriate for clinical use,
a uorinated derivative was developed, (18-F) uoropropyldihydrotetrabenazine, which has proved able to detect abnormal
monoamine neurotransmission depression in Parkinson disease180 and help distinguish diffuse Lewy body dementia from
Alzheimer disease.181 Figure 5 shows a comparison between (F18) uoropropyl-dihydrotetrabenazine PET brain images
obtained in a patient with Parkinson and a healthy control.

Traumatic Brain Injury


Traumatic Brain Injury (TBI) encompasses acute and chronic
sequelae of traumatic injury to the brain. Within a relatively

short term after injury, even within months, symptoms that


range from minimal to persistent somatic, psychological, and
cognitive impairments, termed the postconcussive syndrome,
can develop.182 In the long term, head trauma can result in
chronic traumatic encephalopathy, with symptoms ranging in
severity from headache and attentional disturbance to dementia, Parkinsonism, and behavioral changes183; in more severe
forms, this syndrome is also known as dementia pugilistica.
Even in the acute setting after traumatic injury, global cerebral
hypometabolism can be demonstrated on PET.184,185 Studies
have shown that regional PET hypometabolism can correlate
with persistent symptoms even in the setting of mild injury and
the absence of structural abnormalities on conventional imaging.186,187 Many studies have shown correlation with abnormalities on PET and cognitive function or clinical outcome or
both.187-190 These studies have demonstrated involvement of
different, although often overlapping regions of the brain, such
as the temporal lobes, cingulate gyrus, and cerebellum, which
may be owing to the heterogeneity of the causative injuries. TBI
is pathologically characterized by accumulation of cerebral tau
neurobrillary tangles.182,191,192 There is an interest in establishing novel imaging biomarkers that might predict clinical
outcome in patients with TBI, including agents with sensitivity
for tau193; however, none are yet clinically validated.

Conclusions
PET has spearheaded sciences efforts to unlock the workings
of the human brain in both normal and pathologic conditions.
Although technically challenging, requiring coordinated expertise in physics and instrumentation, radiochemistry, and
biology, PET remains poised to explore new frontiers in
neuroscience. PET will continue to play a prominent clinical
role in intractable epilepsy management and dementia diagnosis. As radiochemistry continues to further evolve and
complement our understanding of molecular and cellular
pathophysiology of disease, novel PET biomarkers of neurologic disease are just on the horizon.

PET brain imaging

457

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