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ARTICLE IN PRESSG ModelAT-6131; No. of Pages 7

Maturitas xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Maturitas

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eview

euroimaging in dementia

yara Valkanova, Klaus P. Ebmeier ∗

epartment of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK

r t i c l e i n f o

rticle history:vailable online xxx

eywords:ementialzheimer’s diseaseewy body dementiaronto-temporal dementia

a b s t r a c t

Over the last few years, advances in neuroimaging have generated biomarkers, which increase diagnosticcertainty, provide valuable information about prognosis, and suggest a particular pathology underlyingthe clinical dementia syndrome. We aim to review the evidence for use of already established imagingmodalities, along with selected techniques that have a great potential to guide clinical decisions in thefuture. We discuss structural, functional and molecular imaging, focusing on the most common demen-tias: Alzheimer’s disease, fronto-temporal dementia, dementia with Lewy bodies and vascular dementia.Finally, we stress the importance of conducting research using representative cohorts and in a naturalis-

ascular dementiaET

tic set up, in order to build a strong evidence base for translating imaging methods for a National HealthService. If we assess a broad range of patients referred to memory clinic with a variety of imaging modal-ities, we will make a step towards accumulating robust evidence and ultimately closing the gap betweenthe dramatic advances in neurosciences and meaningful clinical applications for the maximum benefitof our patients.

© 2014 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Structural imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.1. Alzheimer’s dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. Fronto-temporal dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3. Dementia with Lewy bodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.4. Vascular dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3. Functional and molecular imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. Alzheimer’s dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.1.1. Perfusion SPECT and FDG-PET imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1.2. Amyloid imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.2. Fronto-temporal dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.3. Dementia with Lewy bodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.4. Vascular dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Please cite this article in press as: Valkanova V, Ebmehttp://dx.doi.org/10.1016/j.maturitas.2014.02.016

Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: 123-I-FP-CIT, 123-I labelled ioflupane (DatSCAN®); AD, Alzheimer’s demo establish a registry for Alzheimer’s disease; CT, (X-ray) computed tomography; FTD, fronPA; MCI, mild cognitive impairment; MRI, magnetic resonance imaging; MTA, medial temon-fluent PPA; PET, positron emission tomography; PiB, Pittsburgh compound B; PPA, prv-PPA, semantic variant PPA; VBM, voxel-based morphometry; VD, vascular dementia; W∗ Corresponding author. Tel.: +44 1865 226469; fax: +44 1865 793101.

E-mail address: [email protected] (K.P. Ebmeier).

ttp://dx.doi.org/10.1016/j.maturitas.2014.02.016378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

ier KP. Neuroimaging in dementia. Maturitas (2014),

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

entia; bv-FTD, behavioural variant fronto-temporal dementia; CERAD, consortiumto-temporal dementia; LBD, dementia with Lewy bodies; lv-P, palogopenic variantporal lobe atrophy; NICE, National Institute for Health and Care Excellence; nv-PPA,imary progressive aphasia; SPECT, single photon emission computed tomography;

MH, white matter magnetic resonance hyperintensities.

dx.doi.org/10.1016/j.maturitas.2014.02.016


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ARTICLEAT-6131; No. of Pages 7

V. Valkanova, K.P. Ebmeier

. Introduction

Over the last few years, advances in neuroimaging have gen-rated biomarkers, which increase diagnostic certainty, providealuable information about prognosis, and suggest a particularathology underlying the clinical dementia syndrome. This is andvance over the role imaging plays in simply excluding rare causesf dementia, such as mass lesions [1,2]. Although the use of specificiomarkers is generally limited to research studies, it is likely toranslate into clinical practice with increased standardization andccess to biomarkers.

We aim to review the evidence for established imaging modal-ties, along with selected techniques that have the potential touide clinical decisions in the future, focusing on the most commonementias: Alzheimer’s disease (AD), fronto-temporal dementiaFTD), dementia with Lewy bodies (DLB) and vascular demen-ia (VD). Discussion of other dementia syndromes and the theoryehind the various imaging modalities is beyond the scope of thiseview.

. Structural imaging

.1. Alzheimer’s dementia

In many centres, X-ray computed tomography is the standardnvestigation to exclude any space occupying and mass lesions.n fact, some authors have used this technique to estimate hip-ocampal atrophy and thus provide added information supportinghe diagnosis of Alzheimer’s dementia [3]. However, the struc-ural imaging technique most widely used in clinical research is1-weighted magnetic resonance imaging (MRI). The most char-cteristic feature of AD is early, localized medial temporal lobetrophy (MTA) affecting primarily the hippocampus and entorhinalortex [4–8]. MRI evidence of disproportionate MTA has been incor-orated into revised diagnostic criteria as a topographical markerf downstream neuronal injury [1,2].

In clinical practice visual assessment is used most often. One ofhe more widely validated rating scales is the Scheltens’ MTA rat-ng scale [9], which assesses hippocampal atrophy according to the

idth of the choroid fissure, width of the temporal horn, and heightf the hippocampus, using a 0–4 severity scale. Visual inspectionifferentiates mild AD from normal ageing with a sensitivity andpecificity of 80–85% [9–11]. The specificity of MTA decreases withge because of age-related hippocampal atrophy [12]. In researchtudies, mainly volumetric techniques are used and they appearo correlate well with both neuropathological disease progression13–15] and the degree of cognitive impairment [16,17].

Although MTA has been found in other dementias, includingTD, VD and PD, it is less severe there than in AD when matched forlinical severity [18,19]. Hippocampal atrophy develops graduallytarting about 5 years before diagnosis of AD, while 3 years prior toiagnosis hippocampal volumes are reduced by 10% [19].

In atypical forms of AD, in younger patients, or early in the dis-ase course it is possible to have greater atrophy of the parietalobes and less MTA [20–25]. A rating scale based on the degree of

idening of the posterior cingulate, parietal and parieto-occipitalulci has been developed [26].

Particularly in individuals with MCI, structural imaging providesaluable information about prognosis. Although the significantverlap in volumetric measures between patients with MCI andontrols sets some limitations, a recent meta-analysis of 6 VBMtudies found that decreased grey matter in the left hippocampus


nd parahippocampal gyrus was associated with conversion fromCI to AD [27]. Further, Lehmann et al. [28] found that the proba-

ility of converting from MCI to AD increased with greater baselineTA scores; e.g. after three years, fewer than 40% of patients with

PRESSuritas xxx (2014) xxx–xxx

an MTA score of 0 converted to AD, compared with more than 75%with baseline MTA score of 3.

2.2. Fronto-temporal dementia

FTD encompasses a heterogeneous group of conditions andcan be broadly divided into behavioural variant fronto-temporaldementia (bv-FTD) and primary progressive aphasia (PPA). Bv-FTDis associated with predominant atrophy in the frontal and para-limbic areas, including the anterior cingulate cortex, as well asorbitofrontal and medial frontal cortices and subcortical structures[29–32]. Ratings of orbitofrontal atrophy in conjunction with anexecutive function test classified 92% of patients correctly intobvFTD or AD [33].

PPA is itself categorized into three clinical phenotypes: semanticvariant PPA (sv-PPA), non-fluent PPA (nv-PPA) and logopenic vari-ant PPA (lv-PPA). In semantic variant PPA, there is typically atrophyof the anterior and inferior temporal lobes, including the fusiformgyrus, while the non-fluent variant PPA is characterized by perisyl-vian atrophy and involvement of the anterior insula [31,34,35]. Thelogopenic variant PPA is commonly associated with Alzheimer’stype pathology and the atrophy involves the posterior temporalcortex and inferior parietal lobule [36]. In PPA the atrophy is moreoften asymmetrical, with the left side being more affected [31]. Inaddition to distinct patterns of regional atrophy that are associatedwith each clinical phenotype, rate of atrophy was found to be twiceas great in FTD and SD, compared with AD [37]. However, in theearly stages, functional imaging may be more useful because thestructural scan can be normal [32,38]. The most recently publishedguidelines for FTD proposed, in addition to a clinical diagnosis, evi-dence for abnormalities on either structural or functional brainimaging as a criterion for establishing a diagnosis of ‘probable’ FTD[36,39].

2.3. Dementia with Lewy bodies

DLB is associated with diffuse atrophy, which is greater than incontrols, but less than in patients with AD. Relatively focused dorsalmeso-pontine grey matter atrophy, with a relative sparing of themedial temporal lobes, supports a clinical diagnosis of DLB ratherthan AD [40–42].

2.4. Vascular dementia

Evidence from structural neuroimaging is mandatory for diag-nosing vascular dementia (VD), with MRI being the preferredmodality. Small-vessel disease is the commonest cause of VD [43],although large artery ischaemic disease may lead to VD, as well.

Small-vessel disease is usually defined as lesions involving>25% of the white matter. Signs of small vessel disease on MRIinclude white matter magnetic resonance hyperintensities (WMH),recent small subcortical infarcts, lacunes, prominent perivascularspaces, cerebral microbleeds and atrophy. Their defining featuresare summarized in an excellent paper aiming to provide standardsfor reporting vascular changes on neuroimaging (STRIVE [44]).Although white matter changes can be detected on X-ray CT scans,the tissue contrast tends to be discrete, and this method is lesssensitive than MRI.

White matter lesions appear as bilateral, mostly symmetricalhyperintensities on T2-weighted MRI. They become more commonwith advancing age and are found in 10–90% of cognitively nor-mal elderly depending on the study. Although WMH are strongly


associated with vascular risk factors, as well as predicting anincreased risk of stroke and dementia [45], they are clinically andpathologically heterogeneous [46]. WMH are not specific to vas-cular dementia and can be found in a variety of other conditions


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ncluding leucodystrophies, leucoencephalopathies, inflammatoryonditions (multiple sclerosis) and infections [47]. The relationshipetween vascular damage and cognition is not fully understood,ut it is increasingly recognized that whether cognitive deficitsevelop in the presence of vascular damage depends on the bal-nce between factors conferring resilience (education, premorbidQ) and risk (age, vascular risk factors, and lifestyle). However, as

MH become more extensive they are more likely to be clinicallyignificant [48]. The severity of white matter disease can be gradedisually using established scales such as the Fazekas scale [49].arge irregular periventricular or confluent deep WMH (Fazekasrade 3) are characteristic of VD.

Silent infarcts and lacunes are also common in healthy elderlyeople (between 20 and 50%), but they are associated with an

ncreased risk of future dementia and stroke [50]. Although MRIs more sensitive than CT for detecting ischaemic injury, it wasegative in up to 30% of patients with symptomatic lacunar strokeyndromes, suggesting that it cannot detect all infarcts [51].

Up to 65% of patients with VD and 10–20% of healthy elderlyave microbleeds which on T2*-gradient echo image appear as

ocal hypointensities (typically 2–5 mm, but up to 10 mm) [52,53].icrobleeds related to amyloid angiopathy most commonly have

ortico-subcortical distribution, while microbleeds associated withypertension are located centrally. The two conditions often co-xist [54–56]. Patients with vascular dementia also have globaltrophy, probably due to subclinical diffuse ischaemia, or focal atro-hy corresponding to an area of infarction [57,58].

Finally, it is increasingly recognized that mixed pathologies areommon. VD and AD share risk factors [59,60] and can have a syn-rgistic relationship [61]. This implies that even when extensiveascular damage is suggested by a structural scan, the presence ofixed pathology should be considered.

. Functional and molecular imaging

.1. Alzheimer’s dementia

.1.1. Perfusion SPECT and FDG-PET imagingFunctional and molecular imaging has an important role in the

euroimaging of dementias. Changes in function and molecularomposition of brain tissue typically precede atrophy detectabley structural imaging. Jack et al. [62] have suggested the dynamiciomarkers model of AD: at first markers of amyloidosis becameositive, followed by markers of cortical hypometabolism on FDG-ET, and last, markers of brain atrophy. The characteristic ADatterns of abnormal brain perfusion or metabolism are found

n the association cortex while primary sensory-motor cortex iselatively preserved [63], with a ratio of association cortex activ-ty over primary sensory-motor cortex activity being suggesteds a diagnostic index for AD [64]. Early in the disease course,PECT and FDG-PET show reduction in posterior cingulate and pre-uneus perfusion or metabolism, followed by bilateral posterioremporo-parietal reductions and involvement of the frontal areas indvanced disease [63–65]. The findings in functional scans correlateith CSF biomarkers [66], as well as with cognitive measures [67].

erfusion abnormalities in AD-related regions are predictive of con-ersion from MCI to AD [68–70]. Hypometabolism was found evenn cognitively normal individuals at increased risk of AD [71,72].

An autopsy-confirmed study found that SPECT improves theccuracy of the diagnoses, with a positive scan in patients withossible AD increasing the likelihood of pathologically confirmed


D from 67% to 84% [73]. A recent meta-analysis of 11 studies usingPECT and 20 studies using PET found pooled sensitivity of 80% andpecificity of 85% for SPECT to differentiate patients with AD fromontrols, while PET showed pooled sensitivity of 90% and specificity

PRESSuritas xxx (2014) xxx–xxx 3

of 89% [74]. These results suggest that PET is more sensitive thanclinical assessment in detecting AD (90% vs 81%), while both SPECTand PET are more specific than clinical criteria (85% and 89% vs 70%)[2].

However a prospective community-based study of 102 individ-uals with early-onset dementia found PET to have considerablylower sensitivity and specificity for AD (78% and 81%, respectively)than reported in the meta-analysis [75]. Although the results couldbe explained by sample characteristics (e.g. early-onset dementia),or the lack of pathological confirmation, this study highlights thesignificance of ecologically more valid research with ‘real’ worldsamples.

It is also important to investigate the added value of imagingmarkers above a standard work-up, as well as how imaging mark-ers perform in combination. A study of 154 memory clinic patientsfound that combined imaging (PiB and FDG-PET) led to change in23% of the initial clinical diagnoses, while the diagnosis establishedafter PET remained unchanged in 96% of cases after two years.Combined PiB and FDG-PET contributed to diagnosis in 104 cases,followed by PiB only (29 cases) and FDG-PET only (11 cases) [76].

While both PET and SPECT are good enough to assist in thedifferential diagnosis of dementia [63], SPECT is currently morewidely available. This has been translated into guidelines, with NICEstating that ‘HMPAO-SPECT should be used to help differentiatebetween AD, VD and FTD if the diagnosis is in doubt’ [77]. 18F-FDG-PET is included as a topographical biomarker of neuronal injury inthe revised international diagnostic criteria for AD [1,2]. A recentreview concluded that although studies suggest superiority of PETover SPECT, the evidence base for this is quite limited [78].

3.1.2. Amyloid imagingAmyloid imaging provides direct evidence of the presence of

Alzheimer’s type pathology. A� plaque markers become positiveyears before clinical symptoms and reach a plateau by the timethese appear [62].

The best characterized amyloid PET tracer is Pittsburgh com-pound B (PiB) which is labelled with C-11 and binds mostly tofibrillar �-amyloid. Amyloid PET with PiB has very high sensitivityfor detecting amyloid deposition. More than 90% of patients withAD show increased cortical binding [79], and false–negative casesare reported only rarely [80]. As a result, it has been included in therevised guidelines as a pathophysiological marker of AD [1,2].

Its positive predictive value is low, as some healthy elderly peo-ple show higher cortical binding. The reported proportions vary,but frequencies of 15–30% are most commonly reported. A� depo-sition is affected by the imaging method, the definition of whatconstitutes a positive result, and by the two main risk factorsfor AD, namely age and ApoE genotype [81,82]. The frequency ofamyloid-positive scans increased from 0% below the age of 50 to30% at age 80 [83]. Non-carriers of the allele were less than half aslikely to have a positive scan as ApoE4 carriers (21% vs 49%) [84].Independently of the effect of ApoE4, maternal familial history ofAD has also been associated with higher cortical binding [85,86].

A major disadvantage for the clinical application of PiB PET isthe short half-life of C-11, which limits its use to centres withan on-site cyclotron. However, over the last years tracers labelledwith 18F such as Flumetamol, Florbetapir and Florbetaben havebeen developed. 18F has a longer half-life (110 min), allowing cen-tral production and distribution, which is already making amyloidimaging more widely available [87].

Clinical trials have demonstrated that the new 18F-compoundshave properties similar to PiB. Comparative studies within the same


subjects show excellent correlation between PiB and each of them[88–90], as well as similar effect sizes for distinguishing AD fromhealthy controls [89,91]. In a prospective phase 3 study with Flor-betapir, the PET scan results of 59 patients were dichotomized and


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ompared to their dichotomized CERAD neuritic amyloid plaquecores obtained from autopsy within 1 to 2 years of PET imaging.he study included healthy subjects, as well as patients with AD,D and FTD, with a varying degree of cognitive impairment and

ound a sensitivity and specificity of PET for detection of moderateo frequent plaques of 92–96% and 100%, respectively [92].

Amyloid imaging has very good predictive value for conversiono AD in patients with MCI, as demonstrated in studies with up to

years follow-up [93–95]. Negative scans in individuals with MCIo not discount progression, as other neurodegenerative diseasesithout amyloidosis, such as FTD, cannot be excluded.

Amyloid imaging is also excellent in differentiating AD fromon-amyloid dementias such as FTD [96–98], and there is no uptake

n most cases with PD dementia [99]. However positive scans areommon in DLB [98,100,101] which is consistent with pathologicalndings [102]. This implies that amyloid imaging may be most use-

ul in atypical presentations or in early-onset dementia, when therevalence of AD equals that of FTD and the frequency of amyloideposition in controls is low. Positive scan in cases with exten-ive vascular damage can confirm the presence of mixed pathology,hich would have implications for treatment [103]. For instance,

1% of cases who met DSM-IV criteria for VD and had extensiveMH without large-vessel stroke or macro-haemorrhage were PiB

ositive [104].

.2. Fronto-temporal dementia

The patterns seen on functional imaging in FTD tend to be sim-lar to those seen on structural scans, but they are visible earlier inhe disease course [105]. A study of 134 patients with suspectedTD found that SPECT/PET increased sensitivity of consensus crite-ia from 36.5% to 90.5%, when clinical diagnosis after 2 years wassed as a gold standard [106]. Another study with pathologicallyonfirmed diagnoses of FTD or AD also showed that PET increasesiagnostic accuracy beyond clinical assessment [107].

Amyloid imaging in FTD confirms the lack of amyloid deposi-ion in this condition, with patients showing values of cortical PiBetention close to those found in controls [108].

.3. Dementia with Lewy bodies

There are few publications for perfusion imaging in DLB, but theypical pattern involves occipital reductions, including the primaryisual cortices [109–111]. Although parieto-temporal reductionsre observed in both AD and DLB, occipital hypometabolism dif-erentiated between the two conditions with 90% sensitivity and1–80% specificity [65,109]. Amyloid imaging in DLB shows levelsf cortical PiB retention similar to those observed in AD, with higherccipital retention [100,112].

The most reliable imaging biomarker of DLB is 123-I-FP-CITioflupane) SPECT of the dopamine transporter. Ioflupane showssymmetrical (anterior-posterior) striatal uptake in DLB, witharger decrease of uptake in putamen than in caudate nucleus. Inontrast, age-related nigro-striatal degeneration affects both theutamen and caudate nucleus, and the putamen-to-caudate ratio

s preserved [113]. Normal ioflupane scans in patients with DLBre not common, but have been reported; it is possible that theseatients have exclusive cortical involvement with relative sparingf basal ganglia [114].

Compared with autopsy results, dopamine transporter imagings sensitive and specific (88% and 100%, respectively), whereaslinical diagnosis had a sensitivity of 75% and specificity of only


2% [115]. Abnormal ioflupane scans may be particularly valuablen the group of patients with possible DLB, as this seems to ben unstable diagnosis. A multi-centre study found that only 41%f patients with ‘possible’ DLB have this diagnosis at 12 months


follow up, compared with 93% of patients diagnosed with ‘probable’DLB; scan results can help to classify them correctly [116].

Ioflupane scans have also an important role in the differentialdiagnosis of DLB from AD [117]. A recent meta-analysis of four 123-I-FP-CIT SPECT studies, including a total of 419 patients, reported apooled sensitivity of 86.5% and a specificity of 93.6% for the differ-entiation of DLB from non-DLB, predominantly AD [118]. Howeverabnormal ioflupane binding is less reliable in differentiating DLBfrom FTD, because about 30% of FTD patients were have positiveioflupane scans [119]. Ioflupane scans also cannot differentiatebetween syndromes characterized by dopaminergic loss, includingDLB, Parkinson’s disease, multiple system atrophy or progressivesupranuclear palsy. Reflecting the increasing evidence for the clin-ical utility of ioflupane SPECT, it has been incorporated in reviseddiagnostic criteria for DLB [120]. It has also been recommended byNICE to help with the diagnosis of DLB when the diagnosis is indoubt [77].

3.4. Vascular dementia

In patients with VD and no infarcts on structural imaging, func-tional scans typically show scattered areas of reduced perfusion ormetabolism. The lesions are often multiple, asymmetrical or local-ized in ‘watershed’ regions of the brain [63]. Compared with AD, inVD there is more pronounced hypometabolism in subcortical areasand primary sensorimotor cortex whereas the association areas aretypically less affected [121].

4. Conclusion

At present, neuroimaging is most likely to be used in the dif-ferential diagnosis of dementia, as well as to aid in establishing aprognosis. When disease-modifying treatments become available,this is likely to change, and imaging methods can be used to screenpatients, with function-based and ligand-based techniques havinga particular role in the detection of early changes.

The future of neuroimaging will involve incorporating newmodalities into routine clinical practice. However, introducingimaging methods as routine in a National Health Service requiresa strong evidence base for their clinical utility and added value.When considering the clinical utility of neuroimaging, it is impor-tant to realize that mixed pathologies commonly co-exist in thesame individual, and there is a substantial overlap of pathologi-cal changes even with health. This will impose limitations on thediagnostic performance of any test and implies that a combina-tion of imaging biomarkers will be most useful. Therefore, studiesinvestigating how different modalities perform in combination willbe particularly useful.

In addition, strong evidence can only come from studies usingrepresentative cohorts and conducted in a naturalistic clinicalenvironment. Currently, studies are conducted mainly in highlyspecialized centres and often include subjects from clear-cutdiagnostic groups, which limits the generalizability of results.Establishment of pilot services is crucial, because each clinicalcontext is associated with characteristic variables, such as demo-graphics of the sample, a priori probability of dementia types,frequency of atypical presentations, and clinical expertise of healthcare professionals; all these factors have an impact on the valuethat imaging methods add above routine clinical assessment. If weassess a broad range of patients referred to memory clinic with a


variety of imaging modalities, we will make a step towards accu-mulating reliable evidence and ultimately closing the gap betweenthe dramatic advances in neurosciences and meaningful clinicalapplications for the maximum benefit of our patients.


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ontributors

Vyara Valkanova – first draft (part), revisions (whole). Klaus P.bmeier – first draft (part), revisions (whole)

ompeting interest

Vyara Valkanova – none; Klaus P. Ebmeier – reports consultationees received from Lily in relation to Amyvid TM

unding

Klaus P. Ebmeier – UK Medical Research Council (G1001354),he Gordon Edward Small’s Charitable Trust (SC008962), and theDH Wills 1965 Charitable Trust.

rovenance and peer review

Commissioned and externally peer reviewed.

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Neuroimaging in dementia