KEY POINTS

NEUROIMAGING IN A The AAN

recommends at

DEMENTIA least one

structural scan
in the routine
Maria Carmela Tartaglia, Paolo Vitali, Raffaella Migliaccio, evaluation of
Federica Agosta, Howard Rosen dementia.

A Specific patterns
of atrophy are
ABSTRACT useful in the
As treatment of neurodegenerative disease moves toward therapies aimed at specific differential
molecular abnormalities, the importance of early and accurate diagnosis will increase, diagnosis of
as will the need for sensitive measures for tracking disease progression. Brain imaging, dementia.
using MRI and PET scanning, offers a variety of highly reliable techniques that examine
the structure, chemical content, metabolic state, and functional capacity of the brain.
For all the major neurodegenerative disorders, relatively specific findings can be
identified with some or all of these techniques. New approaches for imaging specific
molecular pathology likely will revolutionize brain imaging and be combined with
established imaging approaches to obtain a complete molecular, structural, and meta-
bolic characterization, which could be used to improve diagnosis, and to stage each
patient and follow disease progression and response to treatment.
Continuum Lifelong Learning Neurol 2010;16(2):153–175.

INTRODUCTION portance of making accurate etiologic

Brain imaging is routinely performed in
evaluation of dementias, but it has tra-
ditionally been viewed as making a small
contribution to clinical care.1 In most
cases, clinicians use brain imaging to
rule out obvious explanatory pathology,
such as tumors, hemorrhages, or other
subacute or chronic pathology. As the
clinical approach to dementia changes
in the future, however, several factors will
require clinicians to rely more heavily on
brain imaging for diagnosis and patient
management. The most important an-
ticipated development will be the use of
treatments targeted at specific molec-
ular pathologies, eg, eradication of toxic
diagnoses to avoid inappropriately ex-
posing patients to potentially dangerous
medications. Parameters obtained from
neuroimaging, such as metabolism or ce-
rebral volume, can be measured much
more accurately than changes in memory
abilities or other clinical factors, making
imaging an attractive technique for mea- 153
suring the response to treatment, both
in research and in clinical practice. In ad-
dition, as reviewed in this chapter, neuro-
degenerative diseases are associated with
the development of pathologic changes
long before the development of functional
impairment (dementia). Thus, neuroim-
aging has a potential role in diagnosing
-amyloid in patients with Alzheimer dementing disorders in very early clini-
disease (AD). This will increase the im- cal or even presymptomatic stages.

Relationship Disclosure: Drs Tartaglia, Vitali, Migliaccio, Agosta, and Rosen have nothing to disclose.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Tartaglia, Vitali, Migliaccio, Agosta, and Rosen
have nothing to disclose.

Copyright # 2010, American Academy of Neurology. All rights reserved.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 " NEUROIMAGING

KEY POINT
For all these reasons, researchers are
A Alzheimer
increasingly turning to neuroimaging to
disease (AD)
shows a establish its role in early and accurate
particular diagnosis as well as to investigate how
atrophy pattern changes in brain structure and function
that includes can be measured over time. A variety of
hippocampus imaging techniques are available. The
and entorhinal goal of this review is to provide a broad
cortex as well overview of the various methods used
as the amygdala, to image neurodegenerative disease.
anterior
parahippocampal COMPUTED TOMOGRAPHY
gyrus, corpus AND MAGNETIC RESONANCE
callosum and its IMAGING
subregions, and
the frontal, Computed Tomography
temporal and CT imaging was the first technique to
occipital lobes. provide a detailed image of the brain and
so has the longest history of use in de-
mentia. CT scanning adequately ad-
dresses the most basic goal for imaging
in neurodegenerative disease, which is
to rule out alternate pathologies; how-
ever, such findings are rare. Although
CT scanning is still regularly used for
diagnostic assessments and for studies
of brain-behavior correlation, research
on most aspects of degenerative demen-
tias has moved away from CT scanning
because this technique typically has
lower resolution than MRI scanning and
is not as sensitive to many types of ab-
normalities seen in neurodegenerative
syndromes.
sulcal size. These changes probably de-
velop secondary to decreases in synap-
tic density, in addition to neuronal loss
and cell shrinkage. Because every neu-
rodegenerative disease has a predilection
for specific brain systems, particularly
early in the course of disease, each is
associated with tissue loss in particular
brain regions. In AD, the medial tempo-
ral lobes, especially the hippocampus
and entorhinal cortex (ERC), are among
the earliest sites of pathologic involve-
ment.2 Accordingly, studies of hippocam-
pal and ERC volumes have repeatedly
shown decreased hippocampal and ERC
volumes in AD compared with age-
matched controls (Figure 8-1).3
Volume loss in AD is extensive and is
not limited to the hippocampus and ERC
but includes the frontal, temporal and
occipital lobes,4 indicating that much of
the brain shrinks in AD. Among the re-
gions outside the medial temporal lobes,
the parietal and posterior superior tem-
poral regions on the lateral cerebral
surfaces, and posterior portion of the
cingulate gyrus on the medial surface
are among the most severely affected

Magnetic Resonance Imaging

154 MRI offers an increasingly diverse ar-
ray of approaches for imaging neurode-
generative diseases, including T1- and
T2-weighted imaging, fluid-attenuated in-
version recovery (FLAIR) (a variation of
T2-weighted imaging), diffusion-weighted
imaging (DWI), diffusion-tensor imaging
(DTI), magnetic resonance spectroscopy,
and functional MRI (fMRI).
Structural MRI/T1-weighted im-
aging. The most common abnormality Coronal MRI through
FIGURE 8-1
detectable using structural imaging in the brain of patient with
Alzheimer disease. Notice
neurodegenerative disease is loss of the enlarged temporal horns due to
brain volume, which is manifested by hippocampal (arrow) atrophy.
decreases in gyral size and increases in

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(Figure 8-2).5 The utility of regional
volume loss in the diagnosis of AD, how-
ever, is still unclear because in most vol-
umetric studies, at least some overlap
exists between patients and controls, so
that imaging measures correctly identify
between 80% and 100% of patients, de-
pending on the study and the region
being measured. Given that most of
these patients are clearly demented at
the time of study, the added value of
imaging in this setting is unclear.
MRI has also been used to study pa-
tients with mild cognitive impairment
(MCI), who have memory concerns and
impairments on cognitive testing that are
not impeding daily function. Patients
with MCI are at high risk for progression
to AD, converting to dementia at a rate
of about 12% to 15% per year. MRI stud-
ies in MCI have shown that hippocam-
pal volumes and cortical volumes in the
parietal and lateral temporal regions
could predict the likelihood of progres-
sion,6 although precise prognostication
in an individual is still not achievable.
KEY POINT
Longitudinal studies have demonstrated
A Behavioral
greater atrophy rates in ERC,7 and the
variant
temporal lobe as a whole8 in both AD frontotemporal
and MCI compared with controls. degeneration is
Structural imaging has also been stud- associated with
ied as a means of differentiating various volume loss in
causes of dementia from each other. This the ventromedial
has been examined extensively in fronto- frontal cortex,
temporal degeneration (FTD), in which the posterior
MRI has revealed unique patterns of brain orbital frontal
atrophy. (See the chapter ‘‘Frontotem- regions, the
insula, and the
poral Degeneration, page 191, for ex-
anterior cingulate
planation and discussion of terminology
cortex.
for FTD). In patients with the behavioral
variant of FTD, frontal lobe volumes are
reduced compared with those of both
AD patients and age-matched controls,
but most striking is the pattern of fron-
tal lobe changes. While some lateral
frontal lobe atrophy occurs with AD,
FTD is uniquely associated with volume
loss in the ventromedial frontal cortex,
the posterior orbital frontal regions, the
insula, and the anterior cingulate cortex
(Figure 8-2).9 These regions are frontal
components of the brain’s emotional

155

FIGURE 8-2 Voxel-based morphometry analysis. A, Volume loss in Alzheimer disease (AD)
compared with controls is not limited to the hippocampus and entorhinal cortex.
Other regions showing reduced volume in AD include the parietal and posterior
superior temporal regions on the lateral cerebral surfaces, and posterior portions of the cingulate
gyrus on the medial surface are among the most severely affected. B, In the behavioral
variant frontotemporal degeneration (FTD), frontal lobe volumes are reduced compared with
age-matched controls. Volume loss occurs in the ventromedial frontal cortex, the posterior orbital
frontal regions, the insula, and the anterior cingulate cortex.

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 " NEUROIMAGING

KEY POINTS
processing systems so that their involve- sonian dementias. In progressive supra-
A Patients with
ment in FTD explains the unique behav- nuclear palsy, third ventricle dilatation
semantic variant
show marked ioral symptoms seen in that disorder. In and midbrain atrophy with shortening of
loss of volume in contrast, patients with the semantic var- the anteroposterior length of the midbrain
the temporal iant of FTD have relative preservation are reportedly characteristic (Figure 8-4).
lobes, in of frontal lobe volumes but marked loss Direct measurement of midbrain size has
particular the of volumes in the temporal lobes, in yielded mixed results, with some studies
neocortex in the particular the neocortex in the tempo- showing good differentiation of progres-
temporal pole. ral pole (Figure 8-3).9 Patients with the sive supranuclear palsy from other de-
A Specific patterns semantic variant of FTD also have atro- mentias, and others showing overlap
of regional phy in the amygdala, which is a critical between syndromes. In corticobasal degen-
volume loss structure for emotional processing.9 eration, classical descriptions have stressed
have been Several studies have highlighted the asymmetric parietal lobe atrophy. How-
described in clinical utility of these patterns of re- ever, more recent analyses have indicated
parkinsonian gional atrophy. For example, frontal lobe that corticobasal degeneration is asso-
dementias. In volumes correctly classify 93% of patients ciated with as much frontal as parietal
progressive with FTD compared with controls.10 Many atrophy, and the diagnostic value of
supranuclear
studies have also demonstrated relation- asymmetric volume loss has been called
palsy, third
ships between local changes in brain vol- into question by recent studies indicat-
ventricle
ume and cognitive or behavioral changes ing that this pattern can be associated
dilatation and
midbrain in dementia. In AD, for example, several with several types of pathology.15 De-
atrophy with studies have found correlations between mentia with Lewy bodies is associated
shortening hippocampal volumes and episodic mem- with diffuse atrophy, and no established
of the ory performance, consistent with the long- pattern is characteristic on structural MRI.
anteroposterior established role for this structure in Some forms of spinocerebellar atro-
length of the memory consolidation.11 Many studies phy are associated with cognitive impair-
midbrain are of non-AD dementias, particularly FTD, ment and are typically associated with
reportedly have yielded findings that shed light on both cerebellar and cerebral atrophy
characteristic. poorly understood brain functions, in- along with caudate and putamen atro-
A In corticobasal cluding language and word access,12 phy in some variants.15
degeneration understanding of facial expressions of T2-weighted imaging, FLAIR, and
(CBD), classical emotion,13 and empathy.14 vascular changes. T2-weighted and
descriptions Specific patterns of regional volume FLAIR images are typically more sensitive
have stressed loss have also been described in parkin- than T1-weighted structural imaging
asymmetric
156 parietal lobe
atrophy, but
more recent
analyses have
indicated that
CBD is associated
with as much
frontal as
parietal atrophy,
and the
diagnostic
value of
asymmetry has
been questioned. MRI coronal (A) and axial (B) view of patient with semantic
FIGURE 8-3
variant. Significant left temporal atrophy with relative sparing
of medial temporal region is present.

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 KEY POINTS
A T2-weighted
and FLAIR
images are
typically more
sensitive than
T1-weighted
structural
imaging to
edema and
gliosis, which
show up as
increased
(bright) signal.
Common
neurodegenerative
FIGURE 8-4 Sagittal and axial MRI sections of a patient with progressive
supranuclear palsy. A, Arrow on sagittal view points to flattening disorders such
of midbrain superior colliculi. The atrophy of the midbrain results as AD and
in a convex upper border of the midbrain with the typical humming bird sign. frontotemporal
B, Arrows on axial view indicate flattened superior colliculi.
degeneration
tend to show
no major
changes on
to cerebral pathology characterized by executive impairment.17 In subcortical vas- T2/FLAIR.
edema and gliosis, which appear as cular dementia, the pattern of white mat- A FLAIR imaging is
increased (bright) signal on T2 weight- ter abnormality can help to identify the very sensitive to
ing. Common neurodegenerative dis- underlying cause. Lesions in periventric- injury caused by
orders such as AD and FTD tend to ular and deep white matter are usually ischemia from
show no major changes on T2/FLAIR, al- associated with small vessel cerebrovas- both small
though these can be seen in some cases, cular disease (eg, systemic hypertension, vessel and large
particularly when severe atrophy is present. vessel disease.
Small vessel
T2/FLAIR imaging is, however, very sen-
disease causes
sitive to injury due to ischemia from both
incomplete or
small vessel and large vessel disease. Small complete
vessel disease causes incomplete or com- infarcts in the
plete infarcts in the white matter or in white matter or
subcortical gray matter nuclei.16 On FLAIR in subcortical
images, incomplete infarcts appear as hy- gray matter
157
perintensities, whereas complete infarcts nuclei. On
present as lacunes, which are hypoin- FLAIR images,
tense to the brain and isointense to the incomplete
CSF (Figure 8-5). Lacunar strokes are infarcts appear
small complete infarcts (2 mm to 15 mm). as hyperintensities,
whereas
Small vessel disease identified on MRI in
complete
the white matter has been called leuko-
infarcts present
araiosis and appears as multiple punc- as lacunes,
tuate or confluent T2 bright lesions. A which are
FIGURE 8-5 Axial fluid-attenuated
mild amount of leukoaraiosis is commonly inversion recovery image hypointense
seen in healthy older adults. Quantitative from a patient with to the brain
MRI studies in nondemented elderly sub- vascular dementia showing multiple patchy
areas of high signal in periventricular and isointense
jects demonstrate that the total volume of white matter. to the CSF.
subcortical lesions correlates with frontal

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 " NEUROIMAGING
KEY POINT
diabetes, hyperhomocysteinemia) or
A Small vessel
acute hypotensive states (eg, orthostatic
disease
identified on hypotension, congestive heart failure,
MRI in the arrhythmias).16 The involvement of sub-
white matter is cortical white matter, often with small
called cortical infarcts, can be caused by cardiac,
leukoaraiosis, aortic, or carotid microemboli, vasculitis,
which appears and cerebral autosomal dominant arterio-
as multiple pathy with subcortical infarct and leu-
punctuate or koencephalopathy.18,19 In vasculitis, MR
confluent angiography shows some abnormalities in
lesions, but the minority of cases in which large vessels
more often as
are involved, and paramagnetic contrast
incomplete
infarcts. It
injection may show brain or vessel wall
is commonly enhancement, but the diagnosis usually
seen in healthy requires angiography or brain biopsy.20
older adults. T2/FLAIR imaging is also sensitive to
microhemorrhages. These are charac-
teristically hypointense lesions because
cerebral iron deposition leads to local
inhomogeneities in the magnetic field.
These may be seen in up to 65% of cases
diagnosed with vascular dementia.21 T2*
gradient-echo images are most sensitive
to these findings (Figure 8-6). In amyloid
angiopathy, unlike hypertension-related
lesions, microhemorrhages are more fre-
quently located at the cortico-subcortical
junctions in frontomesial, frontoorbital,
and parietal regions.22
158
FIGURE 8-6 A, Coronal and (B) axial gradient-echo MR images showing
multiple microhemorrhages.
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T2/FLAIR imaging also reveals some
important findings in non–vascular
degenerative diseases. For example, in
multiple system atrophy (MSA), T2/FLAIR
imaging often shows a posterolateral
putaminal hypointensity, mainly due to
iron deposition, with a hyperintense rim,
mainly due to gliosis. A combination of
T2* gradient-echo sequences and FLAIR
shows fair accuracy in differentiating
MSA from Parkinson disease.15 MSA also
shows degeneration of transverse pon-
tine fibers as the characteristic ‘‘cross’’
sign (also called the hot cross bun sign),
which is also associated with middle ce-
rebellar peduncle hyperintensity and with
pontine atrophy (Figure 8-7).
Limbic encephalopathies often have
T2-weighted medial temporal lobe and/or
patchy white matter hyperintensity
(Figure 8-8).23 Many rapidly progressive
dementias can cause leukoencephalop-
athy, including progressive multifocal leu-
koencephalopathy and leukodystrophies,
or mixed gray and white matter involve-
ment, such as mitochondrial diseases and
intravascular lymphoma.24 Infections and
toxic condtions can also be a cause of
dementia and are discussed in other sec-
tions of this issue. MRI with contrast

FIGURE 8-7 A, Sagittal T1- and (B) axial T2-weighted images of a patient
with multiple system atrophy. Notice the pronounced cerebellar,
cerebellar peduncles, and pontine atrophy. On sagittal view,
notable flattening of the pons is present. On axial view, note the hyperintense
brachium pontis and cruciform pattern (hot cross bun sign) in the pons as a result
of sparing of the pyramidal tracts.
should be used in the evaluation of most
rapidly progressing dementias.
Diffusion-weighted imaging and
diffusion-tensor imaging. DWI is based
on the analysis of the random motion
of water molecules in the brain. DWI
images are grossly normal in most neu-
rodegenerative diseases; however, in
Creutzfeldt-Jakob disease (CJD), decreased
FLAIR coronal view
FIGURE 8-8
showing hyperintense
hippocampi in a patient
with autoimmune voltage-gated potassium
channel limbic encephalitis.
KEY POINT
A DWI is useful
for diagnosing
Creutzfeldt-
Jakob disease
(CJD).
Decreased
diffusion in
cerebral cortex
(called cortical
ribboning) is
associated with
decreases in the
basal ganglia
and is highly
sensitive and
specific for the
diagnosis of
CJD. Variant
CJD is often
associated
with high
diffusion in cerebral cortex (called cortical signals in the
ribboning) with associated decreases in pulvinar region
the basal ganglia is highly sensitive and giving the
specific for the diagnosis of CJD (sensitivity pulvinar sign.
of 91%, specificity of 95%) (Figure 8-9).25
Variant CJD is often associated with high
signals in the pulvinar region.26
Abnormal DWI can also be seen in other
rapidly progressive dementias, including
Bartonella encephalopathy, Wernicke en-
cephalopathy and Wilson disease,27–29
while antibody-mediated encephalopa-
thies and neurofilament inclusion body
dementia can have FLAIR hyperinten-
sity in the cortex and/or deep nuclei. In
these condtions, unlike prion disease, 159
the underlying white matter is also of-
ten involved.30 Seizures, including non-
convulsive status epilepticus, can result
in cortical ribboning on DWI, but this
should resolve a few days after cessation
of seizures.31
DWI images represent an average of
diffusion in the three main directions
(right/left, front/back, up/down), and thus
the signal in each voxel of a DWI image
does not tell about the direction of
movement of the water molecules. An
important variation of DWI is DTI, which
represents the directional diffusion of

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 " NEUROIMAGING

KEY POINT
A DTI represents
the diffusion
of water
in three
dimensions. In
axonal fibers,
an ordered
arrangement
of cells causes
the diffusion
of water to be
significantly
greater along
the axis of
those fibers
(anisotropic
FIGURE 8-9 Axial diffusion-weighted imaging showing cortical ribboning left
diffusion). greater than right in a patient with Creutzfeldt-Jakob disease.

water by tracking movement in three callosum.32 Recently, Zhang and col-

dimensions and providing information
on the predominant direction of diffu-
sion within each voxel. This is done by
measuring the movement of water out
of each voxel in many different direc-
tions, currently as many as 50 or 60. In
certain biological structures, such as ax-
onal fibers, an ordered arrangement of
cells causes the diffusion of water to
be significantly greater along the axis
of those fibers (anisotropic diffusion,
meaning that diffusion is not the same
in all directions). Fractional anisotropy
(FA) is a measure of the degree of an-
160 isotropy of a diffusion process. A value
of zero means that diffusion is isotro-
pic, ie, unrestricted in all directions,
whereas a value of one means that dif-
fusion occurs only along one axis and
is fully restricted in other directions.
Therefore, FA can provide information
on the orientation and integrity of
fibers. Although most of the pathology
in neurodegenerative diseases, particu-
larly in AD, occurs in gray matter, several
recent studies have documented abnor-
malities in white matter in AD, specifically
in temporal lobe white matter, poste-
rior cerebral white matter, and corpus
leagues identified reduced FA in the
portion of the cingulum bundle con-
necting the hippocampus to the poste-
rior cingulate region in patients with
MCI and AD compared with controls. The
use of this measure provided improved
classification of patients from controls
compared with hippocampal volumes
alone.33 White matter tract integrity has
also been correlated with measures of
episodic memory in AD and MCI.34
DTI is also being used more to ex-
amine differences across dementia sub-
types. A recent study found decreased
FA in the parietal lobes in dementia with
Lewy bodies compared with AD, con-
sistent with metabolic studies and the
prominent visuospatial difficulties often
seen in these patients.35 In a recent study
comparing AD and FTD, it was shown
that patients with FTD had reduced FA in
frontal and temporal regions, including
the anterior corpus callosum, bilateral
anterior and descending cingulum tracts,
and uncinate fasciculus, compared to
controls (Figure 8-10A), while patients
with AD had reduced FA in parietal, tem-
poral and frontal regions, including the
left anterior and posterior cingulum tracts,

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FIGURE 8-10 A and B represent anterior to posterior coronal slices of regional
fractional anisotropy (FA) between groups (voxel-wise analysis).
A, FTD<CN shows FA reductions in frontotemporal degeneration (FTD)
relative to normal controls involving the anterior frontal and temporal brain. B, FTD<AD
shows FA reductions in FTD relative to Alzheimer disease (AD) indicating FTD had
significantly lower FA in vast regions of bilateral frontal lobes, including anterior corpus
callosum, bilateral anterior cingulate gyrus, uncinate fibers, and anterior limb of internal
capsule. The areas with significantly decreased FA values are marked in warm colors
with threshold PFDR = 0.05.
CN = cranial nerve.
Figure courtesy of Yu Zhang, University of California, San Francisco.

bilateral descending cingulum tracts, and
left uncinate fasciculus.36 This work dem-
onstrated not only that the location of
white matter abnormalities was specific
for the frontal lobes in FTD (as would be
expected) but also that the magnitude
of white matter changes is larger in FTD
than in AD (Figure 8-10B).
Magnetic resonance spectroscopy
with MRI. In vivo proton magnetic res-
onance spectroscopy (1H MRS) with MRI
allows noninvasive sampling of brain
chemistry by measuring the levels of
relatively few specific metabolites, in-
cluding N-acetylaspartate (NAA), choline,
creatine, lactate, and glutamate. Because
NAA is thought to be a marker of neu-
ronal integrity, many studies have fo-
cused on NAA content in patients with
dementia. In patients with AD compared
with cognitively normal elderly subjects,
NAA is consistently reported as lower in 161
various portions of the brain, particularly
in the parietal gray matter and hippocam-
pus.37 In vascular dementia the greatest
losses occur in the frontal and parietal
cortex.38 Myo-inositol, a marker associ-
ated with gliosis, has also been reported
as high in patients with AD.39 Decreased
NAA and increased myo-inositol have
also been reported in MCI.40
1
H MRS has been used in a few stud-
ies of non-AD dementias, including FTD,41
prion diseases,42 Huntington disease,43
and AIDS dementia complex.44 In one
study comparing AD and FTD patients,

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 " NEUROIMAGING
the NAA/creatine ratio was reduced in
the posterior cingulate cortex in the pa-
tients with AD and FTD/Pick disease, but
the patients with AD showed a greater
decrease posteriorly while the patients
with FTD/Pick complex displayed greater
frontal decrease.41 1H MRS has been used
relatively infrequently for brain-behavior
correlations.
Iron-dependent T2 contrast with
MRI. Iron-dependent T2 contrast has
been reported as increased in a number
of regions in AD, including the hippo-
campus, ERC, globus pallidus, putamen,
and caudate.45 Although the significance
of the increased iron is still being in-
vestigated, a growing body of literature
suggests that altered iron metabolism or
its accumulation is associated with toxic-
ity or cell injury. Susceptibility-weighted
imaging is an emerging technique that
uses the information not only from the
magnitude of a gradient-echo MRI se-
quence signal, but also from the phase of
the signal. The phase shift is strongly
dependent on the susceptibility of the
tissues to the local inhomogeneities in
the magnetic field.
Functional activation using MRI.
fMRI permits the measurement of brain
activity related to cognitive processing
because increased synaptic activity leads
to local increases in blood flow. The
resulting changes in oxyhemoglobin/
deoxyhemoglobin ratio alter the local
162 magnetic properties in the brain,46 re-
sulting in blood oxygen level-dependent
signal. The ability provided by MRI to
indirectly measure synaptic activity in
response to cognitive demands provides
a measure that may be the best correlate
of cognitive performance and a promis-
ing technique for following disease pro-
gression and treatment response. The
tasks can be tailored to examine specific
domains of function pertinent to whatever
subtype of dementia is being studied.
A number of investigators have exam-
ined brain activation patterns in demen-
tia, with complex results. While several
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studies have shown increased activation
in AD or MCI, others have shown a
combination of increased activation in
some regions and decreases in others,
while others have seen only decreases.47
Increases in activation are often inter-
preted as evidence of compensatory pro-
cessing, but whether this is true and the
nature of this compensation are unknown.
fMRI has had limited use in non-AD
dementias. Rombouts and colleagues
studied verbal working memory in early
FTD and AD and found decreased acti-
vation in frontal and parietal regions in
FTD.48 The FTD group displayed a stronger
response in the cerebellum, which was
interpreted as a possible compensatory
mechanism. A recent study also showed
increased temporal lobe activation in
dementia with Lewy bodies compared
with AD on a visual motion processing
task.49 It is not yet clear what parame-
ters predict increased versus decreased
activation for a given cognitive task.
Until this is better understood, the role of
fMRI in diagnosis or monitoring of pa-
tients with dementia will remain unclear.
Resting state functional MRI. The
variability in metabolic activity during
periods when subjects are not actively
engaged in cognitive processing, either
between blocks of trials of a cognitive
task or during passive resting in the MRI
scanner, has also proven relevant to de-
mentia. Several regions across the brain,
often with related functions, covary in
terms of the rise and fall of their blood
oxygen level-dependent signal during
these periods. The resulting networks
of regions seen with this kind of analysis
have been referred to as resting state net-
works, and several networks have been
identified.50 The default mode network,
which includes the posterior cingulate,
inferior parietal, inferolateral temporal,
ventral anterior cingulate, and hippo-
campal regions, has received the most
attention in AD (Figure 8-11), and has
been shown to have decreased activity
in AD and MCI. This is consistent with
 KEY POINTS
A PET is most often
used with [18F]-
fluorodeoxyglucose
(FDG) to measure
brain energy
metabolism.
SPECT is most
commonly used
to study cerebral
perfusion with
compounds such
as HMPAO.
These techniques
FIGURE 8-11 Resting state data of default mode network and some key nodes from a group
analysis of 15 healthy young subjects’ resting-state data. The z-score can theoretically
distribution is shown on the color bar to the right. Key nodes in the network reveal metabolic
are indicated by green arrows. abnormalities in
MPFC = medial prefrontal cortex; PCC = posterior cingulate cortex; RSC = retrosplenial cortex; structurally
IPC = inferior parietal cortex; HC = hippocampus. normal brain.
Figure courtesy of Michael Greicius, MD, Stanford University.
A FDG-PET
demonstrates
reduced
glucose
the structural data reviewed in this potential in dementia were conducted metabolism in
chapter highlighting these regions as be- with metabolic imaging using radioactive the parietal and
ing affected particularly severely in AD. materials. The most commonly used tech- superior/
Other networks may have relevance to niques are SPECT and PET. Both tech- posterior
other dementias. For instance, a ‘‘salience’’ niques can be used to measure a variety of temporal
network that includes the dorsal ante- physiologic parameters in the brain using regions of
rior cingulate and orbital/frontoinsular various chemical compounds. PET is most patients
regions and tracks with emotional mea- often used with [18F]fluorodeoxyglucose with AD.
sures may be more relevant to FTD.51 (FDG) to measure brain energy metab-
The precise functions of these networks olism. SPECT is most commonly used to
and the physiologic basis of alterations study cerebral perfusion with compounds
in their functions have yet to be deter- such as 99mTc-hexamethylpropyleneamine
mined. However, their use in dementia oxime. These techniques theoretically
is attractive because they can be studied provide unique information about brain
in nearly any patient who can have an states relative to structural imaging be- 163
MRI scan, in contrast to the sometimes cause they can show metabolic abnor-
complex paradigms used for fMRI acti- malities in structurally normal brain.
vation studies. FDG-PET demonstrates reduced glu-
cose metabolism in the parietal and
POSITRON EMISSION superior/posterior temporal regions of
TOMOGRAPHY: GLUCOSE patients with AD. (Figure 8-12, top;
METABOLISM AND BRAIN arrows point to regions of hypometabo-
PERFUSION lism). Very early metabolic deficits occur
in AD and in MCI in the medial portion
Positron Emission Tomography of the parietal cortex, the posterior cin-
and Single-Photon Emission gulate, or retrosplenial region.52 Frontal
Computed Tomography lobe hypoperfusion is often also reported
The earliest studies documenting re- in AD but usually in conjunction with
gional abnormalities with real diagnostic temporoparietal abnormalities.

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 " NEUROIMAGING
KEY POINT
Patterns of metabolic abnormality may
A In contrast
differ according to dementia subtype. In
to AD,
frontotemporal contrast to AD, FTD is associated with
degeneration is hypometabolism in the frontal and ante-
associated with rior temporal regions, with relative sparing
hypometabolism of posterior brain regions (Figure 8-12,
in the frontal bottom). Dementia with Lewy bodies
and anterior is associated with decreased occipito-
temporal regions, temporal metabolism compared with
with relative AD, consistent with the increased dif-
sparing of ficulty such patients have with visual
posterior brain
processing.53
regions.
Studies investigating the diagnostic
utility of these findings suggest that they
are helpful in discriminating patients with
clinically diagnosed AD from age-matched
controls as well as from patients with
vascular dementia and FTD.52 A recent
study of AD and FTD patients whose
diagnoses were ultimately confirmed at
autopsy showed that FDG-PET increases
diagnostic accuracy beyond clinical fea-
tures alone.54
Metabolic imaging can also be useful
for prognosis. Some studies have found
164
FIGURE 8-12 FDG-PET in AD and FTD. In AD, notice
reduced glucose metabolism in superior/
posterior temporal and parietal regions
(arrows). In FTD hypometabolism is present in the frontal
and anterior temporal regions, with relative sparing of
posterior brain regions (arrows).
FDG-PET = [18F]Fluorodeoxyglucose–positron emission
tomography; AD = Alzheimer disease; FTD = frontotemporal
degeneration.
Figure courtesy of Gil Rabinovici, MD, University of California, San Francisco.
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that temporoparietal metabolism mea-
sured using FDG-PET can distinguish pa-
tients with MCI with a progressive course
from those with a nonprogressive course.55
Posterior cingulate hypometabolism on
SPECT has also been used to predict
progression in this setting.56
Altered regional brain metabolism has
been linked to specific cognitive and be-
havioral changes in dementia. Haxby and
colleagues used PET to demonstrate that
right-left hemisphere metabolic asym-
metry in AD was correlated with the
degree of language versus visuospatial
impairment.57 Memory impairment has
been linked to hippocampal hypometabo-
lism,58 and behavioral/emotional varia-
bles, such as apathy, have been linked to
hypometabolism in the anterior cingu-
late region.59
Imaging of neurotransmitter sys-
tems with PET. PET and SPECT are
capable of visualizing many physiologic
parameters beyond perfusion and glu-
cose metabolism. One approach that
takes unique advantage of these capa-
bilities is the study of neurotransmitter
systems using molecules that bind to
neurotransmitter receptors or interact
with neurotransmitter systems in other
ways. For example, imaging of the cho-
linergic system in AD is possible using a
variety of agents that interact with ace-
tylcholine receptors and acetylcholines-
terase, a key enzyme whose function
decreases in AD.60 This type of imaging
could be helpful in guiding therapy by
establishing parameters to predict who
would respond best to neurotransmit-
ter manipulation and by following the
effects of treatment. In fact, PET imaging
has shown significant increases in 11C-
nicotine binding sites after 3 months of
treatment with rivastigmine, and this
correlates with improvements on atten-
tional tasks at 12 months.61
Measurement of cholinergic function
also has applications outside the context
of typical AD. For instance, cognitive
deterioration in patients with Parkinson
 KEY POINT
disease may be caused by spread of Lewy included seven patients with a clinical
A PET ligands can
body pathology outside the substantia diagnosis of AD and 12 with FTD. All
be used to image
nigra or the development of superim- patients with AD (7/7) had increased disease-specific
posed AD. In either case, effects on cho- 11C-PiB retention by visual inspection, molecular pathology.
linergic function are likely. A recent PET while most (8/12) patients with FTD and Agents that bind
study with N-[11C]-methyl-4-piperidyl five (5/5) controls had no increase in to plaques
acetate (MP4A), which labels acetylcho- 11C-PiB retention, consistent with the containing -amyloid
line systems, and 18F-fluorodopa (FDOPA) proposal that non-AD dementia will not can be seen
evaluated cholinergic and dopaminergic usually show increased 11C-PiB reten- with radiolabeled
function in Parkinson disease patients tion (Figure 8-13).64 The increased Pittsburgh
with dementia and without dementia.62 11C-PiB retention in the four patients compound B
While FDOPA uptake in the striatum was with FTD may represent AD pathology (11C-PiB) and help
to establish a
decreased in both groups, cortical MP4A
diagnosis of AD.
binding was severely decreased in patients
with Parkinson disease with dementia
compared with controls, but only mod-
erately decreased in patients with Parkin-
son disease alone. The ability to measure
each of these neurotransmitters systems
could help to guide treatments specific
to each system.
Amyloid imaging with PET. The
recent development of new PET ligands
for imaging disease-specific pathology may
revolutionize brain imaging in neurode-
generative disease. Specifically, studies
with agents that bind in vivo to plaques
containing -amyloid, such as radio-
labeled Pittsburgh compound B (11C-PiB)
have demonstrated marked retention of
11C-PiB in the frontal, parietal, tempo-
ral, and occipital cortices as well as the
striatum in patients with AD compared
with controls.52 Because 11C-PiB labels
amyloid plaques that are not normally
present in healthy brains, 11C-PiB im- 165
ages in patients with AD usually appear
dramatically different than images from
healthy controls, allowing easy visual
interpretation of PiB images. The short FIGURE 8-13 Axial slices of mean 11-C Pittsburgh
compound B images (normalized to
half-life of 11C-PiB requires that the PET cerebellum) in patients clinically diagnosed
center have a cyclotron, which may ulti- with AD (top row, N = 27, mean age 67.1+/-9.9), FTD (middle
mately limit the utility of 11C-PiB and row, N = 31, mean age 64.5+/-7.5), and cognitively normal
controls (bottom row, N = 12, mean age 73.9+/-6.1).
favor other agents. Patients with AD show tracer uptake throughout frontal,
Since the first reports on 11C-PiB, sub- parietal, lateral temporal cortex, and striatum, while most
patients with FTD and controls show only mild nonspecific
sequent studies have shown increased tracer binding in white matter.
PiB retention in patients with MCI,63 AD = Alzheimer disease; FTD = frontotemporal degeneration.
and several reports have examined PiB
Figure courtesy of William Jagust, MD, University of California, Berkeley, and Gil
retention in non-AD dementias. A re- Rabinovici, MD, University of California, San Francisco.
cent study by Rabinovici and colleagues

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 " NEUROIMAGING
mimicking the clinical presentation of FTD,
or it may represent coexisting pathol-
ogy. In addition to PiB, other approaches
for imaging specific molecular pathology
in neurodegenerative disease are under
development, thus far only in AD.52
While molecular imaging is a very prom-
ising approach for diagnosis of neu-
rodegenerative disease, results of this
technique should be interpreted cau-
tiously as it gains wider use. The pres-
ence of increased PiB retention should
not be considered tantamount to a diag-
nosis of AD. The few studies in non-AD
dementias have highlighted the fact that
complex results may emerge, and the in-
terpretation of these findings will require
much more study. In addition, 11C-PiB
studies have demonstrated increased
retention in up to approximately 20% to
30% of healthy older individuals who
are cognitively normal.65 Whether such
patients are destined to develop demen-
tia is still an open question. The fact that
increased 11C-PiB retention can occur
in cognitively normal individuals is con-
sistent with pathologic studies indicat-
ing that up to approximately 37% of au-
topsies in patients who were cognitively
normal prior to death show pathology
meeting National Institute on Aging–
Reagan criteria for a high or intermediate
likelihood of AD.66 As the review above
clearly demonstrates, however, many
166 other techniques capable of tracking
function over varying time intervals are
available to image changes in brain oc-
curring secondary to neurodegenera-
tive disease. Techniques for imaging
specific molecular pathology such as
11C-PiB will likely be combined with
one or more of these other imaging
techniques to identify molecular abnor-
malities and to quantify their effects
in the brain. Case 8-1 demonstrates
the utility of combining several imag-
ing techniques to make a more accurate
diagnosis.
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CONCLUSION
Brain imaging offers an increasingly wide
array of techniques for studying the
changes associated with neurodegener-
ative disease (summarized in Table 8-1).
In addition to the approaches highlighted
in this chapter, which primarily utilize
MRI, PET, and SPECT, other approaches
for quantifying changes in the brain, in-
cluding EEG and magnetoencephalog-
raphy, could be considered ‘‘imaging’’
approaches, because they depict regional
changes across the brain; they are, how-
ever, beyond the scope of this chapter.67
Despite the availability of methods for
imaging many aspects of structure and
function, including white matter tract in-
tegrity, neurotransmitter function, task-
related synaptic activity, and chemical
content, the bulk of imaging research in
dementia is still focused on regional ab-
normalities in glucose metabolism, per-
fusion, and tissue content. The simple
goal of making early and accurate diag-
nosis solely with imaging has not been
achieved for the common degenerative
diseases, although DWI has emerged as
a critically important diagnostic tool in
CJD. In certain contexts, such as differ-
entiation of FTD from AD, imaging can
be a valuable addition to the clinical as-
sessment. The arrival of amyloid imag-
ing may herald the emergence of a new
era in which imaging of the specific mo-
lecular abnormality associated with each
degenerative syndrome will be possible.
However, we must be cautious as we
embrace this technology to avoid over-
diagnosis and to recognize the possibil-
ity of multiple metabolic abnormalities
accounting for a patient’s clinical pre-
sentation. The future of brain imaging
will likely involve combinations of imag-
ing techniques to identify the presence of
a molecular abnormality, to gauge its
impact on the brain structure and func-
tion, and to predict and follow the effects
of treatment.
Case 8-1
A 55-year-old left-handed man had a 9-year
history of profound behavioral changes,
including compulsive sorting of recyclable
items, disinhibition, and socially inappropriate
behavior (eg, stripping naked at a family
beach outing, pretending to be blind so
that his dog would be allowed on a train,
hanging a dead bird on a clothesline).
He was insatiable and would eat as long
as food was present, and he would take food
from other peoples’ plates. He occasionally
ate food that was spoiled. His wife FIGURE 8-14 Coronal (left) and axial (right) sections
from T1-weighted MRI.
reported that he had become much
more self-centered and flat in emotional
expression. When his mother, with whom
he was very close, died, he showed no
emotion. He was irritable and occasionally
he became so angry that his wife was fearful
for her safety. She was not able to reason
with him, as he had no insight. He was
distractible and often failed to complete
tasks. He developed several repetitive
motor behaviors, including frequent
yawning, rubbing the edges of his mouth
with his finger, and throat clearing. Past
medical history and family history were
noncontributory.
His neurologic examination was
unremarkable. On neuropsychological
examination, he scored 20/30 on the
Mini-Mental State Examination and showed
deficits in episodic memory, visuospatial
tasks, and executive function. Language
was relatively spared.
MRI demonstrated predominantly
biparietal atrophy (Figure 8-14), and FIGURE 8-15 Results of (A) a Pittsburgh compound B (PiB)
FDG-PET showed a corresponding biparietal
PET scan and (B) 2-[18F]fluoro-2-deoxy-D- 167
glucose–PET scan obtained 27 months after
reduction in glucose metabolism initial presentation. A, PiB scan reveals amyloid in the brain;
(Figure 8-15). PiB PET showed increased warmer colors (eg, red) indicate greater concentrations of
amyloid deposition, and blue indicates the absence of
PiB retention. amyloid. B, The FDG-PET scan shows biparietal
Comment. This patient presented with the hypometabolism. On an FDG-PET scan, warmer colors
indicate greater metabolism, a sign of healthy brain.
classical symptoms of the behavioral variant
of FTD, but the pattern of brain atrophy Figure courtesy of Gil Rabinovici, MD, University of California, San Francisco.

and hypometabolism both suggested a

significant parietal disease, as seen in AD. PiB PET confirmed the presence of -amyloid,
strongly suggesting AD pathology in this case. In retrospect, the poor performance on visuospatial
testing was a clue to the parietal disease. The significance of the -amyloid remains to be clarified.
This case may represent a patient with AD presenting with the symptoms of FTD, or it may
reflect a more complex process, such as the coexistence of two pathologies: those of AD and FTD.
In either case, the identification of specific molecular pathology as seen in this patient will be
critically important as more specific therapies emerge.

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 " NEUROIMAGING

TABLE 8-1 Summary of Imaging Findings in Various Dementias

Mild Cognitive Impairment

(Amnestic–High Frontotemporal
Method Conversion Risk) Alzheimer Disease Degeneration

Standard Atrophy of parietal lobes

structural CT and hippocampus

Standard More overall atrophy and
structural MRI focal atrophy involving
hippocampus, inferior and
middle temporal gyrus,
posterior cingulate, and
precuneus compared to
nonconverters
Atrophy of parietal lobes
and hippocampus and
entorhinal cortex +/-
thinning of posterior
body of corpus callosum;
widespread atrophy
Behavioral variant FTD; focal
pathology in frontal (dorsolateral,
orbital, and medial frontal cortices)
and anterior temporal regions;
anterior temporal lobe greater
on the left than on the right
side in semantic variant;
left-sided inferior frontal and
insular atrophy in PNFA

Diffusion-weighted
imaging

Diffusion-tensor Reduced FA in portion Alteration in temporal Decreased FA in superior

imaging of cingulum connecting white matter, posterior
hippocampus to posterior cerebral white matter, and
cingulate corpus callosum; reduced
FA in portion of cingulum
connecting hippocampus
to posterior cingulate
longitudinal fasciculus
connecting frontal and parietal
regions in behavioral variant FTD;
decreased FA in inferior
longitudinal fasciculus in
semantic variant

Perfusion MRI Reduced cerebral Arterial spin labeling

perfusion in medial and combination of decreased frontal
lateral parietal, superior perfusion + preserved parietal
temporal, and lateral perfusion in frontotemporal
frontal lobes lobar degeneration

Magnetic resonance Decreased NAA and Diffuse decreased NAA/Cr

spectroscopy increased myo-inositol
168 Functional MRI Decreased hippocampal
(active and activation during memory
resting states) tasks; increased activation
in similar regions used by
controls as well as activation
of areas not used by controls
ratio; focal decrease
NAA/Cr in parietal gray
matter and hippocampus;
high myo-inositol
Increased activation in Decreased activation in
similar regions used by frontal and parietal
controls as well as activation regions; increased cerebellar
of areas not used by activation
controls; decreased activation
in medial temporal areas
during memory tasks

Resting state: decreased

activity in default mode
network of the posterior
cingulate cortex, inferior
parietal, inferolateral
temporal, ventral anterior
cingulate cortex and
hippocampus

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Vascular Lewy Body Corticobasal Creutzfeldt-Jakob Progressive
Dementia Dementia Syndrome Disease Supranuclear Palsy

Diffuse atrophy Asymmetric frontal Third ventricle

and/or parietal dilatation and
atrophy significant midbrain
atrophy, especially of
the anteroposterior
diameter

Hyperintensity of
cortical gyri (cortical
ribboning), the striatum
(caudate and putamen),
and/or thalamus in sCJD;
hyperintensity in pulvinar
(pulvinar sign) in vCJD

Decreased FA in
parietal lobes

Decreased NAA/Cr
ratio in frontal
and parietal cortex
but no significant
losses in medial
temporal lobes

Increased temporal
169
lobe activation on a
visual-processing
task

continued on next page

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 " NEUROIMAGING

TABLE 8-1 Continued

Mild Cognitive Impairment

(Amnestic–High Frontotemporal
Method Conversion Risk) Alzheimer Disease Degeneration

[18F]Fluorodeoxyglucose Hypometabolism in the Reduced glucose metabolism Frontal hypometabolism

PET inferior parietal, posterior
cingulate, and medial
temporal region;
temporoparietal alterations
for distinguishing mild
cognitive impairment
with progressive course
in parietal and superior/posterior
temporal regions; early
changes in posterior cingulate
cortex and precuneus; in
advanced stages of AD,
frontal lobe hypoperfusion
in behavioral variant FTD,
anterior temporal with
semantic variant, and left
perisylvian with PNFA

Neurotransmitter Changes in neurotransmitter

systems imaging function
using PET ligands

Amyloid imaging Increased PiB signal Retention of 11C-PiB in Most do not show uptake
using PET the frontal, parietal,
temporal, and occipital
cortices and striatum

Perfusion with SPECT Hypoperfusion in inferior Temporoparietal Anterior temporal and

(eg, with HMPAO)
parietal lobule, angular hypoperfusion frontal hypoperfusion
gyrus, and precuneus;
temporoparietal
hypoperfusion more
likely to progress to AD

T2-Weighted/proton Posterior portion of Increase of signal intensity

density/FLAIR corpus callosum may be seen in the
hyperintense subcortical white matter
of atrophied gyri,
extending into deep white
matter; corpus callosum
can appear atrophic either
anteriorly or diffusely

170

CT = computed tomography; MRI = magnetic resonance imaging; FTD = frontotemporal degeneration; PNFA = progressive
nonfluent aphasia; sCJD = sporadic Creutzfeldt-Jakob disease; vCJD = variant Creutzfeldt-Jakob disease; FA = fractional
anisotropy; NAA = N-acetylaspartate; Cr = creatine; AD = Alzheimer disease; PET = positron emission tomography;
PiB = Pittsburgh compound B; SPECT = single-photon emission computed tomography; HMPAO = hexamethylpropyleneamine
oxime; FLAIR = fluid-attenuated inversion recovery; CSF = cerebrospinal fluid.

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Vascular Lewy Body Corticobasal Creutzfeldt-Jakob Progressive
Dementia Dementia Syndrome Disease Supranuclear Palsy

Decreased
occipitotemporal
metabolism

Hypoperfusion: left SPECT with presynaptic

anterior thalamic dopamine transporter
lesions; patchy (123I-FP-CIT): reduced
regions of striatal uptake of
hypometabolism dopamine or its
presymptomatic
transporters

FLAIR: hyperintensities Pulvinar sign (greater

(if incomplete) and hyperintensity of
hypointense to the posterior thalamus
brain and isointense relative to anterior
to the CSF if lacunes; putamen); CJD
small vessel disease
in white matter is
called leukoaraiosis
(multiple punctuate or
confluent lesions);
CADASIL: confluent
lesions in periventricular
white matter, characteristic
white matter lesions in 171
temporal poles and in the
external capsule and
striatocapsular lacunae and
microhemorrhages

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 " NEUROIMAGING

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