Imaging, 23 (2014), 20120015

NEURORADIOLOGY

What is the role of neuroimaging in dementia? A review

L NARAYANAN, MRCP, FRCR and A D MURRAY, FRCR, PhD
Division of Applied Medicine, Aberdeen Biomedical Imaging Centre, University of Aberdeen,
Aberdeen, UK
Summary
Structural brain imaging is recommended in patients with dementia by all current

guidelines.
Brain imaging cannot diagnose dementia but can suggest the most likely

underlying neuropathology in a demented patient.

Alzheimers disease is the commonest cause of dementia and usually co-exists with

other pathologies, most often cerebrovascular disease.

Frontotemporal dementias are a heterogeneous group of neuropathologies that

typically cause asymmetric frontal, anterior temporal and/or insular atrophy.

Dementia with Lewy bodies is caused by the same pathology as Parkinsons

disease, and there is clinical overlap.

Cerebrovascular disease is associated with vascular risk factors, increases linearly

with age and, typically, is manifest as white matter ischaemic change and/or
lacunar infarcts.
There are no currently available disease-modifying treatments for dementia.
The prevalence of dementia is doubling every 20 years, as people live longer and
health and social care resources will soon become insufficient.

doi: 10.1259/img.20120015
2014 The British Institute of
Radiology

Cite this article as: Narayanan L, Murray AD. What is the role of neuroimaging in dementia? A review. Imaging
2014;23:20120015.

Abstract. The worldwide prevalence of dementia is estimated

to be 36.5 million with an additional 7.7 million new cases
every year. In the UK alone, the prevalence is close to a million.
Dementia continues to have huge implications for health and
social care. Even in affluent societies like the UK, the needs will
soon outstrip available resources. Dementia, defined as
a syndrome of progressive memory and cognitive decline that
affects the individual in activities of daily life is still
fundamentally a clinical diagnosis. However, neuroimaging
has increasingly come to play a major role not only in clinical
practice but also in research and clinical trials. Current
guidelines in the UK recommend structural brain imaging in
all patients with a new diagnosis of dementia. Largely, this is to
exclude treatable causes like subdural haematoma. However,
imaging can also assist in further characterization of certain
types of dementia. This article is an update on the various
imaging modalities available in current clinical practice in the
work-up of dementia in the UK and briefly touches on the
newer technologies being explored in dementia research.
The worldwide prevalence of dementia is estimated to
be 36.5 million with an additional 7.7 million new cases
every year. In the UK alone, the prevalence is close to
Address correspondence to: Professor Alison Murray. E-mail: a.d.
murray@abdn.ac.uk

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a million. Although a doubling of cases every 20 years

was predicted, more recent surveys and studies have
shown varying rates of incidence of dementia all over the
world from remaining stable,1 to falling2,3 to rising.4
Several factors have been attributed to this: implementation of public health initiatives reducing the cardiovascular risk factors in the population; improved
education; and better awareness among people regarding
healthier lifestyle choices. People also are more educated
than generations before, contributing to cognitive reserve
in later life.5 It is suggested that the criteria to assess if
a population is ageing should be revisited and are too
simplistic in current definitions.6
However, it cannot be denied that, with rising population, the average prevalence of dementia will increase
worldwide before it stabilizes and eventually declines.
Dementia continues to have huge implications for health
and social care. Even in affluent societies like the UK, the
needs will soon outstrip available resources. In 2006, the
cost of dementia in the UK was 539 per second, totalling
17 billion per year (Alzheimers Society7). The topic has
gained enormous attention recently, as there is a global
concerted effort to meet the challenges. This has heralded
a new era of multicentre collaborative large data sets like
the Alzheimers Disease Neuroimaging Initiative, which
are freely available to researchers making high-quality
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L Narayanan and AD Murray

research possible at relatively less costs. Developing

technologies in structural and molecular neuroimaging
have driven research to focus on earlier diagnosis of atrisk individuals who could be targeted for future early
intervention in the prodromal phase before irreversible
neuronal loss.
Dementia, defined as a syndrome of progressive memory and cognitive decline that affects an individual in his/
her activities of daily life, is still fundamentally a clinical
diagnosis. Where does a clinical radiologist fit in?
Current guidelines in the UK recommend structural
brain imaging in all patients with a new diagnosis of
dementia. This is largely to exclude other treatable causes
of dementia, such as normal pressure hydrocephalus,
subdural haematoma or an intracranial mass lesion,
rather than in the diagnosis of dementia itself (Scottish
Intercollegiate Guidelines Network,8 National Institute
for Health and Clinical Excellence9). Brain CT should
suffice in most cases. However, the sheer volume of scans
presents us with other problems, primarily that of incidental findings, which are unrelated to the clinical
condition (Royal College of Radiologists10).
However, in an affected individual, imaging can play
a very important role in indicating the most likely underlying pathology or for further characterization of the
type of dementia.

Alzheimers disease pathology

In neurodegenerative dementias, the underlying pathology is that of abnormal protein accumulation. In
Alzheimers disease (AD), two proteins are implicated,
tau and b-amyloid (Ab). Mutations in the genes regulating
amyloid precursor protein and presenilins 1 and 211 have
been identified to be the cause of abnormal Ab metabolism
resulting in amyloid plaque formation. The tau protein in
its hyperphosphorylated form is implicated in intracellular
neurofibrillary tangles.12 In sporadic AD, apolipoprotein 34
(APO34) is implicated with early onset of AD (less than
65 years), more cognitive impairment and faster clinical
decline. APO34 is also associated with negative outcomes in
other neurodegenerative diseases, such as Parkinsons disease,13 suggesting 34 positivity indicates brain vulnerability
to multiple pathological processes, not just AD (Table 1).
The sequential involvement of brain regions in AD was
documented by early pathology-based studies.14,15 It was
observed that neurofibrillary tangles were initially seen
within the neurons of the entorhinal cortex in the medial
temporal pole, a region by virtue of connection with the
hippocampus, playing an important role in laying down
new memory. Subsequent hippocampal involvement
affects episodic memory, and as disease progresses to
involve the other regions of the temporal lobe and related
neocortex, cognition, language, attention and executive
functions are affected severely, thereby affecting the activities of daily living.
In vivo assessment of disease burden using biomarkers
has redefined the criteria for clinical diagnosis,16 with
a recent revision of these criteria by the National Aging
SummitAmerica.17,18 AD neuropathology is not exclusive to ADit is also seen in normal brain ageing, can
coexist with other neuropathologies19 and can occur in
prodromal phases of AD up to 15 years prior to the onset
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Table 1. Types of dementia

Primary dementias
Alzheimers disease
Late-onset ADmost common form, 6070% of all
dementias
Early-onset ADunder 65 years of age, chromosome
14 implicated, Downs syndrome
Familial ADinheritable form present in at least two
generations within families
Dementia with Lewy bodies and Parkinsons disease
dementia
Frontotemporal dementia
Mixed dementiamore than one form of pathology,
e.g. Lewy bodies with AD
Less common forms
Progressive supranuclear palsy
Huntingtons disease
Secondary dementias
Vascular/multi-infarct dementia
Vascular with AD
Trauma
Alcohol
Medications
CreutzfeldtJakob disease
Intracranial mass lesions
Normal pressure hydrocephalus
Subdural haematomas
Infectionsprimarily HIV
Vitamin deficienciesvitamins E, B, and folic acid are
implicated
AD, Alzheimers disease; HIV, human immunodeficiency
virus.

of clinical dementia. Disappointing and even detrimental

results in some of the pharmacological trials have shifted
the focus from interventions in the clinical phase to
modifying factors in the pre-clinical phase. Imaging biomarkers have shown promising correlation with laboratory biomarkers, playing an important role in identifying
high-risk pre-clinical patients who might benefit from
early intervention.

Imaging biomarkers
Structural imaging in Alzheimers disease
Both CT and MRI have been used in structural brain
imaging. Atrophy of the medial temporal cortex and
hippocampi is the structural hallmark of AD.20,21 This can
be easily recognized on CT (Figure 1). Progressive atrophy on successive studies in any one individual is more
accurate than in a single study.22 The rate of volume loss in
the hippocampi is three times greater per annum in AD
than in controls.23 The resolution of images and the differentiation of greywhite matter on MRI is far superior
to CT (Figure 2), especially with the ability to acquire
multiple sequences, and is recommended as the first
choice of investigation in the national guidelines. However, most National Health Service departments will have
inadequate MRI capacity for the growing number of
patients with dementia and will even struggle to accommodate CT requests. There are different manual and
automated methods available for hippocampal volumetry in a research context (such as FreeSurfer, surfer.nmr.
mgh.harvard.edu/), which are freely available but not
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Imaging in dementia

Figure 1. CT in a patient with Alzheimers disease (AD)

showing hippocampal atrophy in (a) axial and (b) coronal
images; (c) MRI in a patient with AD again showing
hippocampal atrophy in coronal images.

currently appropriate for routine clinical use. Visual

grading methods of hippocampal atrophy24 are, however, useful and able to predict those with cognitive impairment who will progress to AD.25

Molecular imaging in Alzheimers disease

There are two main categories. Non-specific molecular
imaging with regional cerebral blood flow (rCBF) single
photon emission CT (SPECT) or 18F-fludeoxyglucose positron emission tomography (18FDG PET) (Figure 2ac) and
amyloid-specific imaging demonstrating intracranial Ab
deposition.
Specific Ab ligands, such as 11C-Pittsburg compound B
11
( C-PIB),26 18F-florbetapir and 18F-flutemetamol,27,28
demonstrate intracranial amyloid deposition, the earliest

pathological process, pre-dating clinical AD by many

years, even decades. PIB imaging correlated well with
amyloid deposition; however, its use is limited by several
factors. Many subjects with PIB uptake did not progress
to AD and some clinically behaving like AD did not show
PIB uptake. There is no difference in the late-onset and
early-onset groups, whereas on FDG PET, as expected,
uptake was reduced more in the early-onset group. There
is poor correlation with the degree of cognitive decline,
making it difficult to monitor the effect of therapies. In
addition, there is poor correlation with hippocampal
volume, the hallmark of AD.29 In practical terms, 11C-PIB
is limited by a short half-life of 20 min, making an on-site
cyclotron essential. 18F-tagged ligands have a half-life
of 110 min, facilitating widespread clinical availability.
18-Fluorine amyloid PET ligands such as 18F-florbetapir
and flutemetamol have recently been approved by the US
Food and Drug Administration for clinical use for a specific indication where patients with progressive cognitive
decline are being evaluated.30,31 Tau-specific tracers are
under development and are close to clinical availability.
Non-specific molecular imaging using rCBF SPECT and
FDG PET have been in clinical practice for a long time.
These demonstrate reduced perfusion and decreased glucose uptake, respectively, which is not specific to AD.
However, region-specific reductions in the temporal lobes
and posterior cingulate disproportionate to atrophy are
associated with rising cerebrospinal fluid total and phosphorylated tau.3234 Quantitative analysis of FDG PET and
SPECT data has made image analysis, now widely available on scanner workstations, more accurate and allows
comparison of cases with control populations.35
The precise role of amyloid and tau in the pathogenesis
of AD is not entirely clear although tau correlates more
closely with measures of cognitive decline. They usually
co-exist and probably work synergistically in contributing to cognitive decline.

Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) accounts for about
1015% of the dementia population and is clinically
characterized by cognitive impairment with visuospatial

Figure 2. (a) Hexamethylpropylene amine oxime (HMPAO) single photon emission CT (SPECT) in a normal control. (b) HMPAO
SPECT in Alzheimers disease demonstrates typical reduction in perfusion in the temporal lobes, especially medially. (c) CT in the
same patient demonstrating hippocampal atrophy. L, left; max, maximum; min, minimum; R, right; roi, region of interest; s.d.,
standard deviation.

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impairment, visual hallucinations, motor Parkinsonian

features, executive dysfunction and fluctuation in cognition and arousal. Rapid eye movement sleep behaviour
disorder, severe neuroleptic sensitivity and reduced striatal dopamine transporter activity on molecular neuroimaging are supportive features.36
DLB is pathologically characterized by dopaminergic
cell loss, a feature that it shares with Parkinsons disease (PD) and PD dementia. There is pre-synaptic terminal accumulation of a-synuclein particles that
aggregate to form intracellular Lewy bodies. a-Synuclein is analogous to Ab in AD and can exist as
oligomers, fibrils and aggregates. Small oligomers are
thought to be the most neurotoxic. These mainly occur
in the cerebral cortex and limbic system. In PD, they
exist in the substantia nigra, pars compacta and
nigrostriatal projections. Recent work has increased the
understanding of genetic associations of DLB and PD.37
PD dementia is pathologically and clinically indistinguishable from DLB, apart from the fact that, in PD,
motor symptoms pre-date cognitive decline.36,38
Although the diagnosis of DLB will often be obvious
clinically, it may be unclear in a substantial minority of
patients, when neuroimaging may help.

Structural imaging in dementia with Lewy bodies

Structural MRI using voxel-based morphometry has
demonstrated variable regional brain atrophy with some
studies reporting cortical atrophy in the insula, frontal,
inferior parietal, temporal and occipital cortices,39,40
whereas a larger study has differentiated DLB from AD
with more atrophy of the hypothalamus, basal forebrain,
mid-brain, caudate and the putamen and, importantly,
relative preservation of the medial temporal lobe and
hippocampi.41 The rate of progressive atrophy is increased when compared with normal controls, exaggerated if AD co-exists but much lower than in AD. Visual
hallucinations and visuoperceptual deficits, a characteristic clinical feature of DLB, does not seem to correlate with
occipital lobe involvement42 but correlation with other
regions probably involved in visual processing and executive functions have been reported, as in the inferior
frontal lobe. If present, hippocampal atrophy is seen in
the anterior subfield (CA1),43 whereas, in AD, CA2 and
CA3 is more affected, potentially differentiating AD from
DLB on high-resolution MRI.
Other MR methods, such as diffusion tensor imaging
(DTI), arterial spin labelling (ASL) and MR spectroscopy (MRS) have been used to compare DLB with
AD. In general, these demonstrate abnormalities in
the visual association cortex and posterior putamen
in DLB compared with abnormality in the medial
temporal lobe and precuneus in AD, and it is likely
that best discrimination will come from incorporation
of data from more than one sequence or imaging
modality.43

of the occipital cortex and more extensive defects in DLB

than in AD.4446 Molecular imaging specific to DLB
includes dopaminergic, cholinergic and cardiac imaging.
A dopaminergic pre-synaptic ligand, 123I b-carbomethoxy3-b-(4-iodophenyltropane) fluoropropyl (FP-CIT), is used
in SPECT studies reflecting dopaminergic neuronal loss by
decreased uptake in the putamen and caudate nuclei when
compared with controls and AD (Figure 3). Visual image
analysis is adequate to make this distinction, justifying
routine use in clinical practice,47 as recommended by both
the National Institute for Health and Care Excellence in the
UK and the European Federation of Neurological Sciences
in Europe. Quantitative analysis of FP-CIT images using
shape analysis is as accurate as expert observer assessment
and more reproducible.48 However, as would be expected,
there is poor distinction between Parkinson syndromes.
Cholinergic neuronal loss and reduced pre-synaptic
choline acetyltransferace activity is seen in both DLB and
AD. Using specific cholinergic ligands, on PET and
SPECT, demonstrates differential uptake with reductions
in the medial occipital cortex in DLB and temporal lobe in
AD.49 There is cardiac sympathetic denervation in Lewy
body disease, which pre-dates neuronal loss.50
This can be measured using 123I metaiodobenzylguanidine
(MIBG), an analogue of noradrenaline, which demonstrates
the cardiac innervation in relation to the mediastinum.
Several studies have demonstrated reduced uptake distinguishing DLB from AD in patients with demetia.51
MR methods like DTI, ASL MR and MRS are being
studied within the realm of research.

Frontotemporal dementia
This is a heterogeneous group of diseases accounting
for 5% of all dementias, which demonstrate degeneration
of the frontal and/or anterior temporal lobes and insula.
Clinical presentation is often in the fifth or sixth decade,
at least 10 years younger than AD, and patients have
a family history in about 50% of the cases.52 Several
subtypes are recognized, categorized based on the protein involved:

Molecular imaging in dementia with Lewy bodies

On hexamethylpropylene amine oxime (HMPAO)SPECT and FDG PET, findings may not be reliably distinguishable from AD in a single patient. However, with
the aid of quantitative image analysis, there is involvement
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Figure 3. FP-CIT. (a) Normal example of symmetrical uptake in

the caudate heads and putamen bilaterally; (b) absent uptake
in the putamen in a patient with dementia with Lewy bodies.
FP-CIT is a dopaminergic pre-synaptic ligand, 123I b-carbomethoxy-3-b-(4-iodophenyltropane) fluoropropyl.
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Imaging in dementia

Figure 4. CT showing atrophy in (a) asymmetric right

frontal lobe atrophy in
frontotemporal dementia
(FTD); (b) hexamethylpropylene amine oxime single
photon emission CT showing asymmetric anterior
hypoperfusion in FTD, comparison with normal database indicates frontal and
temporal defects, where
perfusion is reduced between 2 (green) and 3
(blue) standard deviations.

1. frontotemporal lobar degeneration (FTLD)tau, including tauopathies such as progressive supranuclear

palsy, corticobasal degeneration and Picks disease
2. FTLDtransactive DNA-binding protein 43-related
abnormalities; a subgroup may also have motor
neuron disease53
3. FTLDfused in sarcoma protein.54
Clinically, depending on the main presenting feature,
they are categorized as
1. behavioural variant frontotemporal dementia (bvFTD),
characterized by marked behaviour and personality
disorder
2. semantic frontotemporal dementia (FTD)a type of
primary progressive aphasia with progressive loss of
semantic knowledge for words, objects and emotions
3. non-fluent verbal primary progressive aphasia
(nfvPPA), a disorder of speech production and expressive language.

Structural imaging in frontotemporal dementia

On CT and structural MRI, there are characteristic atrophy patterns differentiating between the various types
as detailed below.
1. bvFTDfrontal and temporal lobe involvement; in
particular, the ventromedial frontal cortex, the posterior orbital frontal regions, the insula bilaterally and
the anterior cingulate cortex55,56 (Figure 4)
2. svPPAprogressive anterior temporal atrophy56,57
3. nfvPPAleft perisylvian atrophy; in particular, left
frontal operculum52,56 (Broca areas 44, 45, and 47).

Molecular imaging in FTD

Both FDG PET and rCBF SPECT will show asymmetric
anterior metabolic or perfusion defects, respectively
(Figure 4),44,58 distinguishing FTD from AD, which shows
posterior defects. Because frontal defects on molecular

Figure 5. (a) MRI T2 weighted

(T2W)perivascular spaces (PVS)
in basal ganglia; (b) MRI T2W
PVS in centrum semiovale; (c) MRI
fluid-attenuated inversionrecoverywhite matter hyperintensities; (d) MRI T2Wlacune; (e)
MRI T2*solitary subcortical cerebral microbleeds in an elderly
patient presenting with transient
ischaemic attack; (f) CT showing
areas of reduced density in both
hemispheres typical of white matter ischaemic change.

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L Narayanan and AD Murray

Figure 6. Hexamethylpropylene
amine oxime (HMPAO) single photon emission CT (SPECT) in a patient
with mixed vascular disease and
Alzheimers disease. (a) Reduced
blood flow in both the frontal
and parietal lobes, especially on
the left; (b) the same on parametric
images providing an overall view;
(c) HMPAO SPECT in a patient with
pure vascular disease; (d) note
normal hippocampal volumes in
the same patient on CT.

imaging are non-specific and can occur in cerebrovascular

disease, head injury and depression, it is important to have
structural images for correlation, and if only one modality
is to be used, it should be structural. A combination of
structural and molecular imaging has good specificity in
distinguishing FTD from AD with different patterns of
atrophy and uptakes.5961

Vascular dementia
Vascular dementia is the most common secondary
cause of dementia. Large cortical infarcts, lacunar infarcts
(or lacunes), white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), perivascular spaces (PVSs) and
macrohaemorrhages are signs of cerebral vascular disease.
Of these, PVSs, WMHs, lacunes and CMBs62 (Figure 5)
have been firmly established as biomarkers of cerebral
small vessel disease, which may or may not be symptomatic. These are commonly seen in routine clinical
practice in examinations of people aged over 65 years.
These appearances do not, however, equate to a diagnosis
of dementia. Of all the features, WMHs, also known as
leucoencephalopathy, unidentified bright objects and
white matter lesions, appear to be the main predictor of
cognitive impairment and risk of dementia.63 WMHs are
associated with vascular risk factors, such as hypertension
and impaired glycaemic control,64 as well as with adverse
outcomes such as stroke, dementia and death.65 They are
predominantly supratentorial in distribution, having a
predilection for the frontal lobes and periventricular white
matter and are associated with executive dysfunction and
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impaired fluid intelligence, features that characterize

normal cognitive ageing.6668
PVSs are microscopic spaces in the brain parenchyma
surrounding penetrating arteries. These spaces contain
interstitial fluid and are separated from the subarachnoid
space and cerebrospinal fluid (CSF) by the pial lining (glia
limitans).69 They are commonly seen in the basal ganglia
surrounding the lenticulostriate arteries and in the centrum
semiovale following penetrating arteries from the convexity. They are also seen in the mid-brain and hippocampi.

Figure 7. (a) Fluid-attenuated inversionrecovery (FLAIR)

showing high signal in the caudate and putamen in sporadic
CreutzfeldtJakob disease; (b) FLAIR showing high signal in
the pulvinar of the thalami in the variant form of
CreutzfeldtJakob disease.

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Imaging in dementia
Table 2. Summary table
Dementia

Alzheimers disease

DLB

FTD

Vascular dementia

Structural imaging, CT/MRI Molecular non-specific

Hippocampal, medial
temporal lobe,
posterior cingulate
gyrus and
posteromedial
parietal
lobe atrophy on MRI
and CT
Atrophy in insula,
hypothalamus, midbrain, caudate,
putamen and anterior
hippocampi (CA1
volume)40
Variable
predominantly
anterior frontal,
temporal and insular
atrophy
CTcortical infarct,
macrohaemorrhage,
WMH, lacunes
MRI above 1 PVS, CMB

Molecular specific

Research

11

Tau-specific ligands,
MRI-BOLD, fMRI, MR
perfusion, MRS, DTI,
VBM

SPECT perfusion
FDG PETb glucose
uptake in medial
temporal lobe and
hippocampi

C-PIB,
F-florbetapirc
uptake in amyloid
plaques

SPECT

FP-CIT uptake in
Diffusion MR, MRS,
putamen and caudate fMRI, ASL MR, DTI
Cholinergic
PET/SPECT in
medial occipital lobe
123
I MIBG cardiac
uptake
_
fMRI, DTI

FDG PET in visual

cortices

FDG PET and SPECT

anterior frontal and
temporal uptake

18

FDG PET and rCBF SPECT _

anterior and
periventricular

CJD
sCJD

MRI signal on T2W

and DWI in the
caudate and cortex
(cortical ribboning)
vCJD
MRI on T2W and
DWI in the pulvinar of
thalami
Autoimmune
MRI signal on T2W
FDG PET uptake in
encephalitis-related
and FLAIR in the
the medial temporal
dementia
mesial temporal lobe
lobe
, decreased; , increased; ASL MR, arterial spin labelling MR; BOLD, blood oxygenation level dependent; CJD, CreutzfeldtJakob
disease; CMB, cerebral microbleeds; DLB, dementia with Lewy bodies; DTI, diffusion tensor imaging; DWI, diffusion-weighted
imaging; FDG, fludeoxyglucose; FLAIR, fluid-attenuated inversionrecovery; fMRI, functional MRI; FP-CIT, dopaminergic presynaptic ligand 123I-b-carbo-methoxy-3 b-(4-iodophenyltropane) fluoropropyl; FTD, frontotemporal dementia; MIBG, metaiodobenzylguanidine; MRS, MR spectroscopy; PET, positron emission tomography; PIB, Pittsburgh compound B; PVS, perivascular
spaces; rCBF, regional cerebral blood flow; sCJD, sporadic form of CreutzfeldtJakob disease; SPECT, single photon emission CT;
T2W, T2 weighted; VBM, voxel-based morphometry; vCJD, variant form of CreutzfeldtJakob disease; WMH, white matter
hyperintensity.
a
SPECTradiotracer is 99mTc hexamethylpropylene amine oxime.
b
FDG PETradiotracer is 18F-FDG.
c
Recently approved by the US Food and Drug Administration for clinical use in specific cases, primarily to exclude Alzheimers
disease.

Cerebral macrohaemorrhages centred in the basal

ganglia are characteristic of hypertension-associated bleeds
from lenticulostriate arteries and lobar haemorrhages are
secondary to cerebral amyloid angiopathy. CMBs are seen
in the brains of normal older people70 and are also an
accepted biomarker of cerebrovascular disease, including
amyloid angiopathy. However, there is evidence that
CMB at different locations could be associated with different risk factor profiles.71,72

Structural imaging in cerebrovascular disease

CT and MRI are both useful for demonstrating evidence of cerebrovacular disease (CVD), but MRI is more
sensitive. On CT, they are seen as focal (PVS and lacune)
or diffuse (WMH) hypodensities. On MRI, PVSs and
lacunes are best seen on T2 weighted (T2W) sequences as
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tubular or focal rounded bright spots and crescentric or

large oval bright foci, respectively. WMHs are hyperintense on T2W and fluid-attenuated inversionrecovery
(FLAIR) sequences. CMBs are seen as round dark spots
on gradient echo sequences like T2* or susceptibility
weighted imaging. Cerebral micro- and macrohaemorrhage features are commonly seen in basal ganglia
(hypertension) and in the lobes (probably secondary to
amyloid angiopathy). They can be measured using semiquantitative visual rating scales or quantitative voxelbased methods.7274

Molecular imaging in cerebrovascular disease

rCBF SPECT and FDG PET characteristically show
defects in a patchy predominantly anterior distribution,
and these correspond with WMHs on MR and the
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Table 3. Imaging in dementia research
Structural imaging
Functional MRIresting state BOLD functional
connectivity
MRI perfusion
MR spectrocopy
Diffusion tensor imagingto assess structural integrity
Quantitative brain volume and other biomarkers, such
as WMHs by volumetric measures or voxel-based
morphometry (visual ratings commonly used in
research often have significant inter-rater reliability)
Molecular imaging specific to AD
PET amyloid imaging (recently approved for clinical use)
PET tau imaging
Imaging biomarkers of neuronal dysfunction
18
FDG PET
rCBF SPECT
AD, Alzheimers disease; BOLD, blood oxygenation level
dependent; 18FDG, 18F-fludeoxyglucose; PET, positron emission tomography; rCBF, regional cerebral blood flow; SPECT,
single photon emission CT; WMH, white matter
hyperintensity.

impairments of executive function.75 This is distinct from

AD, in which the defects are predominantly posterior.
However, molecular imaging alone is not sufficient and
structural correlation is necessary.
It is, however, important to bear in mind that AD and
CVD are the two most common underlying pathologies
for cognitive decline in the elderly and usually co-exist
(Figure 6). Studies investigating the contribution of
these two underlying pathologies have found that AD
changes on brain imaging are the main predictors of cognitive decline in normal ageing76 or that post-mortem AD
changes are the main predictors of ante-mortem cognitive
impairment and dementia,77 and, so, the presence of vascular change on imaging does not equate with a diagnosis
of vascular dementia.

Imaging in other dementias

Although, as detailed in Table 1, there are various less
common causes of dementia, here we highlight imaging
in a few causes where the clinical picture is unusual or
atypical. Two such conditions are highlighted as important for the radiologist: CreutzfeldtJakob disease (CJD)
and limbic encephalitis-related dementia.
Both sporadic (sCJD) and variant (vCJD) forms of CJD
cause rapidly progressive cognitive impairment, and vCJD
typically has an early age of onset.78,79 Characteristic
neurological and electroencephalogram features will be
recognized by neurologists, but imaging may provide the
first clue. T2 and FLAIR images show typical high signal
in the pulvinar of the thalami in vCJD,80 which is virtually
pathognomonic, and in the caudate heads and cortex
(cortical ribboning) in sCJD,81 features which are best
seen using diffusion-weighted imaging82 (Figure 7a,b).
Limbic encephalitis, now referred to as autoimmune
dementia,83 comprises a heterogeneous group of disorders that can cause cognitive impairment, delirium and
even seizures. Approximately 50% are responsive to steroids, especially where there is a subacute onset and
fluctuating symptoms. MRI findings may show high
signal on T2W and FLAIR in involved brain areas.
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Usually, the limbic structures are involved and according

to a recent quantitative study, specifically, the amygdala.84 Recent studies suggest that one reason for this
variable presentation could be attributed to the type of
autoantibody involved. Autoantibodies against intracellular antigens appear to be closely associated with
changes in the mesiotemporal lobe on FDG PET (hypermetabolism) and are associated to a lesser extent on MRI
(high signal on T2W and FLAIR). This pattern is not seen
in the type where the antibodies are against neuronal cell
surface antigen.85 Some studies have reported a combination of mesiotemporal hypermetabolism and profound
occipital hypometabolism as being a recognizable feature
on FDG PET.86 In the presence of neuron-specific CSF
autoantibodies, up to 50% of the cases may be part of
a paraneoplastic syndrome secondary to an underlying
malignancy. Whole body FDG PET is appropriate to
identify an occult malignancy.87

In summary
With the rapid rise in the prevalence of dementia in our
ageing population, radiology departments face an exponential rise in referrals for brain imaging in patients with
dementia. The modality and criteria for imaging are
largely restricted by the resources available locally and
are expected to be driven by the local departmental policy. The focus of guidelines is still on ruling out reversible
and curable causes, rather than diagnosing a specific
subtype of dementia. Nevertheless, knowledge of easily
recognizable distinguishing features and the relative roles
of structural and molecular imaging can provide early
diagnostic information of the likely underlying neuropathology (Table 2).
The pressure for effective therapeutic interventions,
especially earlier in the pre-clinical phase of neurodegenerative dementias, has driven neuroimaging in research and clinical trials. Imaging findings correlate
closely with neuropathology and can be used for not only
population selection but also measuring treatment response. Many imaging techniques, including functional
MRI, MRS, MR perfusion and ASL MR, continue to be
evaluated (Table 3). Newer modalities such as PET MRI
and fast field cycling MR are likely to have application in
future. Although availability of amyloid tracers for PET
promised more specific diagnosis of AD, this has not
translated into patient benefit. It is likely that amyloid
accumulates early, is neither specific nor sufficient for a diagnosis of AD and that development of tau tracers will be
more informative. Future imaging approaches that quantify abnormalities on multiple modalities and take account
of patient characteristics are likely to be closer to the truth.
When disease-modifying treatments become available,
neuroimaging is expected to play a key role and what are
currently emerging techniques in research may soon very
well be a part of routine clinical practice.

Acknowledgments
A special thanks to Dr Fergus McKiddie (physicist), Dr Roger
Staff (physicist), Dr Jack Straiton (consultant radiologist) and
Imaging 2014, 23, 20120015

Imaging in dementia
Leslie Lovell (principal technologist) who were of immense
help in obtaining the images for the article.

20.

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