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Neurobiology of Aging xxx (2015) 1e8

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Neurobiology of Aging

journal homepage: www.elsevier .com/locate/neuaging

Progressive cortical thinning and subcortical atrophy in dementiawith Lewy bodies and Alzheimer’s disease

Elijah Mak a, Li Su a, Guy B. Williams b, Rosie Watson c,d, Michael J. Firbank d,Andrew M. Blamire e, John T. O’Brien a,*

aDepartment of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UKbDepartment of Clinical Neurosciences, Wolfson Brain Imaging Centre, University of Cambridge, UKcDepartment of Aged Care, The Royal Melbourne Hospital, Melbourne, Australiad Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, UKeNewcastle Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle, UK

a r t i c l e i n f o

Article history:Received 13 October 2014Received in revised form 16 December 2014Accepted 30 December 2014

Keywords:DementiaAlzheimer’s diseaseLewy bodiesMRINeuroimagingAtrophy

* Corresponding author at: Department of PsychiatrUniversity of Cambridge, Box 189, Level E4 Cambridgbridge, CB2 0SP, UK. Tel.: þ44 01223 760682; fax: þ4

E-mail address: john.obrien@medschl.cam.ac.uk (J

0197-4580/$ e see front matter � 2015 Elsevier Inc. Ahttp://dx.doi.org/10.1016/j.neurobiolaging.2014.12.038

a b s t r a c t

Patterns of progressive cortical thinning in dementia with Lewy bodies (DLB) remain poorly understood.We examined spatiotemporal patterns of cortical thinning and subcortical atrophy over 12 months in DLB(n¼ 13), comparedwith Alzheimer’s disease (AD) (n¼ 23) and healthy control subjects (HC) (n¼ 33). Ratesof temporal thinning in DLB were relatively preserved compared with AD. Volumetric analyses subcorticalchanges revealed that the AD group demonstrated significantly increased hippocampal atrophy (�5.8%)relative to the HC (�1.7%; p < 0.001) and DLB groups (�2.5%, p ¼ 0.006). Significant lateral ventricularexpansionwas also observed in AD (8.9%) comparedwith HC (4.3%; p< 0.001) and DLB (4.7%; p¼ 0.008) attrend level. There was no significant difference in subcortical atrophy and ventricular expansion betweenDLB and HC. In the DLB group, increased rates of cortical thinning in the frontal and parietal regions weresignificantly correlated with decline in global cognition (Mini-Mental State Examination) and motordeterioration (Unified Parkinson’s Disease Rating Scale 3), respectively. Overall, AD and DLB are charac-terized by different spatiotemporal patterns of cortical thinning over time. Our findings warrant furtherconsideration of longitudinal cortical thinning as a potential imagingmarker to differentiate DLB from AD.

� 2015 Elsevier Inc. All rights reserved.

1. Introduction

Dementia with Lewy bodies (DLB) is the second leading cause ofdegenerativedementia inolderpeopleafterAlzheimer’sdisease (AD),accounting for up to 15% of cases confirmed at autopsy (Geser et al.,2005; McKeith et al., 1996; Vann Jones and O’Brien, 2014). Becauselow sensitivity for the diagnosis for DLB remains a problem (Nelsonet al., 2010), there is a need for the development of reliable imagingmarkers to help distinguish DLB from other subtypes of dementia.

Cortical thickness is increasingly recognized as a more preciseparameter of age-associated decline in gray matter compared withthe voxel-based morphometry technique (Cardinale et al., 2014;Hutton et al., 2009). In a previous study, we found a greaterextent of cortical thinning in the AD group affecting predominantlytemporoparietal areas, whereas DLB was characterized withcortical thinning in posterior structures (Watson et al., 2014). Thisfinding is consistent with a growing literature of reduced global

y, School of Clinical Medicine,e Biomedical Campus, Cam-4 01223 336968..T. O’Brien).

ll rights reserved.

atrophy in DLB compared with AD (Mak et al., 2014), whereas thepreservation of the medial temporal lobe in DLB has been incor-porated as a supportive feature in the revised criteria for thediagnosis of DLB (McKeith et al., 2005).

As with our previous investigation, most of the imaging studiesinDLBhavebeencross-sectional, andnostudy todatehas investigatedthe longitudinal progression of cortical thinning in DLB. To addressthis gap in the present literature, our aim in this studywas to comparethe progression of cortical thickness over a 12-month period in ADand DLB and similarly aged healthy control subjects (HC). Based onearlier cross-sectional findings (Mak et al., 2014), we hypothesizedthat DLB would have significantly lower rates of cortical thinningcompared with AD, particularly in the temporal lobe.

2. Methods

2.1. Subjects, assessment, and diagnosis

Thirty-six subjects with probable AD (McKhann et al., 1984) and35 with probable DLB (McKeith et al., 2005) were recruited from acommunity dwelling population of patients referred to local old age

E. Mak et al. / Neurobiology of Aging xxx (2015) 1e82

psychiatry, geriatric medicine, or neurology services as previouslydescribed (Watson et al., 2012). Subjects underwent clinical andneuropsychological evaluations at baseline and follow-up at 1 year.Thirty-five similarly aged control subjects were recruited from rel-atives and friends of subjects with dementia or volunteered viaadvertisements in local community newsletters. For the purpose ofthe present study, we included only subjects with magnetic reso-nance imaging (MRI) assessments from both baseline and 1-yearfollow-up. Of the 36 AD subjects, 25 were included after 11 wereunable to participate in the follow-up assessment. Of the 35 DLBsubjects, 14 were included after 12 declined to participate as they ortheir caregivers felt they were too unwell, and 9 subjects had died.However, there were no significant differences in age, gender,educational level, Unified Parkinson’s Disease Rating Scale Part III,Neuropsychiatric Inventory (NPI), or cognitive scores between theDLB subjects who dropped out and the DLB subjects who wereincluded in the present study (Table 2). Of the 35 HC subjects,33 were included in the present analyses after 2 declined toparticipate because of other reasons. The research was approved bythe local ethics committee. All subjects or, where appropriate, theirnearest relative, providedwritten informed consent. At baseline andfollow-up assessments, global cognitive measures included theCambridge Cognitive Examination (CAMCOG) (Huppert et al., 1995),which incorporates the Mini-Mental State Examination (MMSE)(Folstein et al., 1975) in addition to a number of subscales assessing

Table 1Demographics, clinical, and neuropsychological measures

HC DLB

N 33 13Gender (M:F) 20:13 12:1Age (y) 76.7 � 5.3 77.0 � 8.Education (y) 11.8 � 2.6 10.6 � 1.Disease duration (mo) 52.2 � 20ChEI (%) 76.92

BADL 17.41 � 1UPDRSBaseline 1.9 � 1.8 27.7 � 8.Follow-up 2.1 � 2.0 32.6 � 13Change �0.2 � 2.0 �4.9 � 8.

NPI totalBaseline 21.1 � 16Follow-up 24.8 � 14Change �3.7 � 17

CogFluctBaseline 8.1 � 3.4Follow-up 7.8 � 5.4Change �0.1 � 4.

MMSEBaseline 29.2 � 0.9 21.3 � 6.Follow-up 29.2 � 0.9 19.8 � 5.Change �0.1 � 1.0 2.6 � 2.9

CAMCOGBaseline 97.8 � 3.3 69.9 � 18Follow-up 98.6 � 2.8 66.8 � 17Change �0.8 � 2.50 5.8 � 10.

BVMT totalBaseline 18.9 � 6.7 6.23 � 6.Follow-up 21.9 � 5.8 7.8 � 7.7Change �3.0 � 5.3 �0.1 � 4.

Interscan interval (d) 370.9 � 13.3 379.1 � 1

Values expressed as mean � 1 standard deviation.Key: AD, Alzheimer’s disease; BADLS, Bristol Activities of Daily Living Scale; CAMCOG, Camwith Lewy bodies; HC, Healthy control; MMSE, Mini-Mental State Examination; NPI totaScale.

a c2dDLB, AD, and control subjects.b Analysis of variancedHC, DLB, and AD.c Kruskal-Wallis test.d Student t testdAD and DLB.e Wilcoxon rank-sum testdAD and DLB.

domains including orientation, language,memory, attention, praxis,calculation, abstract thinking, and perception. Visuospatial memorywas assessed with the Brief Visuospatial Memory Test (BVMT)(Benedict et al., 1996). Motor parkinsonism was evaluated with theUnifiedParkinson’sDiseaseRating Scale Part III (MovementDisorderSociety Task Force on Rating Scales for Parkinson’s Disease, 2003).For subjects with dementia, neuropsychiatric features were exam-inedwith theNPI (Cummings et al.,1994), and cognitivefluctuationswere assessed with the cognitive fluctuation scale (Walker et al.,2000). Functional ability was assessed with the Bristol Activities ofDaily Living Scale (Bucks et al., 1996).

2.2. MRI acquisition

Subjects underwent both baseline and repeat MR imaging witha 12-month interval. At each time point, subjects underwentT1-weighted MR scanning on the same 3T MRI system using an8-channel head coil (Intera Achieva scanner, Philips MedicalSystems, Eindhoven, the Netherlands). The sequence was a stan-dard T1-weighted volumetric sequence covering the whole brain(3D magnetisation prepared rapid acquisition gradient echo,sagittal acquisition, 1 mm isotropic resolution, and matrix sizeof �240 [anterior-posterior] �240 [superior-inferior] �180 [right-left]; repetition time ¼ 9.6 ms; echo time ¼ 4.6 ms; flip angle ¼ 8

�;

SENSitivity Encoding [SENSE] factor ¼ 2).

AD p-value

2313:10 c2 ¼ 5.28, 0.07a

3 76.5 � 5.4 F2,68 ¼ 0.03, p ¼ 0.97b

9 11.3 � 3.8 p ¼ 0.16c

.4 51.8 � 26.5 p ¼ 0.96d

91.30 c2 ¼ 1.44,p ¼ 0.23a

0.17 14.09 � 7.87 p ¼ 0.23e

0 4.7 � 4.1 p < 0.01c

.2 5.7 � 4.8 p < 0.01c

4 �1.0 � 2.4 p ¼ 0.09e

.8 19.4 � 12.4 p ¼ 0.81e

.9 19.7 � 15.0 p ¼ 0.30e

.4 �0.3 � 11.8 p ¼ 0.50d

2.8 � 3.6 p < 0.01e

1.8 � 3.3 p < 0.01e

4 1.0 � 4.6 p ¼ 0.52d

3 20.9 � 4.0 p ¼ 0.80d

8 18.8 � 4.2 p ¼ 0.60d

2.0 � 3.2 p ¼ 0.63d

.0 69.2 � 11.3 p ¼ 0.90d

.9 62.2 � 14.4 p ¼ 0.42d

8 7.0 � 10.2 p ¼ 0.74d

7 4.2 � 2.7 p ¼ 0.51e

5.2 � 2.6 p ¼ 0.51e

5 �1.0 � 2.7 p ¼ 0.48d

8.8 379.6 � 17.8 p ¼ 0.21c

bridge Cognitive Examination; CogFluct, Cognitive Fluctuation Scale; DLB, demential, Neuropsychiatry Inventory Part III; UPDRS III, Unified Parkinson’s Disease Rating

Table 2Demographics and clinical characteristics of DLB subjects

DLBdropped-out DLBreturned p-value

N 21 14Gender (M:F) 14:7 13:1 c2 ¼ 3.3, 0.07a

Age (y) 79.1 � 6.2 77.2 � 8.0 p ¼ 0.43b

Education (y) 11.0 � 3.0 10.5 � 1.9 p ¼ 0.69c

UPDRS 25.1 � 12.3 27.2 � 7.9 p ¼ 0.58b

NPI total 21.4 � 18.1 21.5 � 16.1 p ¼ 0.70c

CogFluct 4.6 � 3.3 8.4 � 3.4 p < 0.01b

MMSE 19.7 � 4.7 21.2 � 6.0 p ¼ 0.42b

CAMCOG 66.2 � 14.0 69.9 � 17.3 p ¼ 0.49b

Values expressed as mean � 1 standard deviation.Key: CAMCOG, Cambridge Cognitive Examination; CogFluct, Cognitive FluctuationScale; DLB, dementia with Lewy bodies; MMSE, Mini-Mental State Examination; NPItotal, Neuropsychiatry Inventory Part III; UPDRS III, Unified Parkinson’s DiseaseRating Scale.

a c2 test.b Wilcoxon rank-sum test.c Student t test.

E. Mak et al. / Neurobiology of Aging xxx (2015) 1e8 3

2.3. Image analysis

Cortical reconstruction and volumetric segmentation of MRIscans were processed on the sameworkstation using the FreeSurfer5.3 image analysis suite (http://surfer.nmr.mgh.harvard.edu/). Thetechnical details are described previously (Fischl and Dale, 2000;Fischl et al., 1999). The initial processing of T1-weighted MRIimages, for each subject and each time point, includes the followingsteps: removal of non-brain tissue, automated Talairach trans-formation, segmentation of the subcortical white matter, and deepgray matter volumetric structures, intensity normalization, tessel-lation of the gray matter and white matter boundary, automatedtopology correction, and surface deformation to optimally place thegray matter and white matter and gray matter and cerebrospinalfluid boundaries. The cortical thickness is calculated as the closestdistance from the gray and/or white matter boundary to the grayand cerebrospinal fluid boundary at each vertex. All surface modelsin our study were inspected for accuracy, and manual correctionswere performed in the event of tissue misclassification and/orwhite matter errors. However, 3 subjects (2 AD, 1 DLB) still hadextensive pial and/or white matter surface errors and wereexcluded. The data set for all subsequent analyses comprised 33 HC,23 AD, and 13 DLB.

Subsequently, for the longitudinal processing, an unbiasedwithin-subject template space (Reuter and Fischl, 2011)was createdusing robust inverse consistent registration (Reuter et al., 2010).Several processing steps, such as skull stripping, Talairach trans-formations, atlas registration, as well as spherical surface maps, andparcellations were then initialized with common information fromthe within-subject template, significantly increasing reliability andstatistical power (Reuter et al., 2012). The cortical thickness mapswere smoothedusing a 15-mmfullwidth at halfmaximumGaussiankernel to reduce local variations in the measurements.

In addition, the following volumetric measures at both time-points were automatically obtained using FreeSurfer: total intra-cranial volume, lateral ventricles, and 7 subcortical structuresincluding the thalamus, caudate, putamen, pallidum, hippocampus,amygdala, and the nucleus accumbens.

2.4. Statistical analyses

2.4.1. Demographic and clinical measuresStatistical analyses were performed with the STATA 13 (http://

www.stata.com/) software. The distribution of continuous vari-ables was tested for normality using the Skewness-Kurtosis test andvisual inspection of histograms. Parametric data were assessed

using either t tests or analysis of variance for continuous variables.For nonparametric data, Kruskal-Wallis test was used. c2 testswere used to examine differences between categorical measures.For each test statistic, a 2-tailed probability value of <0.05 wasregarded as significant.

2.4.2. Cortical thickness comparisonsFor each hemisphere, vertex-wise comparisons of percent

change of cortical thickness (PcCTh) among the subject groups wereperformed using the longitudinal 2-stage general linear model inFreeSurfer (Reuter et al., 2012). The PcCTh was the dependentfactor, and the diagnostic group was the independent factor.Additionally, we examined the correlations of PcCTh with cognitivedecline (baseline scoredfollow-up score). To assess the involve-ment of PcCTH in disease severity, we assessed correlations withchange scores of the UPDRS. In all imaging analyses, age and genderwere included as nuisance covariates, and family-wise error (FWE)cluster-wise correction using Monte Carlo simulations with 10,000iterations were applied to correct for multiple comparisons (Hagleret al., 2006).

2.4.3. Longitudinal atrophy of subcortical structuresTo reduce the number of comparisons, we derived a total volume

for each structure by combining the volumes from both hemispheres.For each subject, we first calculated the absolute difference involumes between both times (volume follow-up � volume baseline),before dividing by the volume at baseline ([volume follow-up �volume baseline]/volume baseline) to quantify the amount of atrophywith respect to baseline, before multiplying by 100 to derivea percentage change score: ([volume follow-up � volume baseline]/volume baseline)�100%. Subsequently, groupdifferences inpercentagechangeof subcortical volumeswere testedwithanalysisof covariance,controlling for age, gender, and the average of total intracranialvolumes at both time-points. Post hoc Tukey-Kramer pair-wisecomparisons were subsequently tested between each group.

3. Results

3.1. Subject characteristics

The demographic and clinical data for dementia and controlsubjects are summarized in Table 1. Subject groups were wellmatched for age, gender, and educational level, and there was nodifference in inter-scan intervals among all subject groups(p ¼ 0.21). As expected, the DLB group had significantly higherUPDRS scores than the AD and HC groups at both time points.Functional ability, Bristol Activities of Daily Living Scale was similarin DLB and AD (p ¼ 0.23). Disease duration was comparable in bothDLB (52.2 months) and AD (51.8 months; p ¼ 0.96), and the pro-portion of subjects on cholinesterase inhibitors was also similar(p ¼ 0.23). There were no significant differences in changes of NPI(p ¼ 0.50), CogFluct (p ¼ 0.52), and between DLB and AD.

3.2. Longitudinal analyses of cognitive decline in DLB and AD

AD and DLB did not differ on global cognitive measures such asMMSE and CAMCOG at baseline or follow-up. Although both DLBand AD performed poorer over time, the decline in global cognitiondid not differ between groups. BVMT scores were similar for bothgroups at baseline and follow-up, including change scores.

3.3. Comparisons of longitudinal cortical thinning: AD versus HC

Compared with HC, the AD subjects had significantly greaterPcCTh in the bilateral frontal and temporoparietal cortices: left

E. Mak et al. / Neurobiology of Aging xxx (2015) 1e84

precuneus, left rostral middle frontal gyrus, left isthmus cingulate,left temporal pole, left superior parietal gyrus, left superior frontalgyrus, left inferior parietal gyrus, left middle temporal gyrus, leftcaudal middle frontal gyrus, left cuneus, right superior parietalgyrus, right precuneus, right superior frontal gyrus, right para-central gyrus, and right middle temporal gyrus. Compared with AD,no increased rates of cortical thinning were found in the HC group(Fig. 1; Supplementary Table 1; FWE Monte Carlo cluster-wisecorrected).

3.4. Comparisons of longitudinal cortical thinning: AD versus DLB

Compared with DLB, the AD subjects had significantly greaterPcCTh in the left middle and superior temporal gyrus, extending tothe left lingual gyrus. No increased progressive cortical thinningwas found in the DLB group compared with AD (Fig. 1;Supplementary Table 1; FWE Monte Carlo cluster-wise corrected).

3.5. Comparisons of longitudinal cortical thinning: DLB versus HC

There were no significant differences in PcCTh in any regionalareas between the DLB and HC groups.

3.6. Clinical and cognitive associations of cortical thinning

The anatomic results for the vertex-wise correlational analysesare displayed in Fig. 2; Supplementary Table 2; controlled for ageand gender, and FWE Monte Carlo cluster-wise corrected. In theDLB group, increased PcCTH in the left frontal lobe was significantlycorrelated with decline in MMSE scores, CAMCOG Orientation, andExpressive Language performances. Decline in UPDRS was alsosignificantly correlated with increased rates of thinning in the rightsuperior parietal region. In the AD group, increased PcCTH in thebilateral frontal regions were significantly correlated with declinein BVMT scores. No significant correlations between rates of corticalthinning and cognitive decline were demonstrated in the HC group.

Fig. 1. Vertex-wise comparisons of progressive cortical thinning between (A) AD and HC, (BCarlo simulation (10,000) iterations and thresholded at a corrected p-value of 0.01 (Z ¼ 2.0).scale of p values (�log10). Abbreviations: AD, Alzheimer’s disease; DLB, dementia with Lewinterpretation of the references to color in this figure, the reader is referred to the Web ve

3.7. Longitudinal comparisons of subcortical atrophy andventricular expansion

Table 3 and Fig. 3 show the percentage change in subcorticalvolumes between baseline and follow-up. After Bonferronicorrection for multiple comparisons, the AD group demonstratedsignificantly increased longitudinal hippocampal atrophy (�5.8%)relative to the HC (�1.7%; p < 0.001) and DLB groups (�2.5%,p ¼ 0.006). Significant lateral ventricular expansion was alsoobserved in AD (8.9%) compared with HC (4.3%; p < 0.001) and DLB(4.7%; p ¼ 0.008) at trend level. There was no significant differencein subcortical atrophy and ventricular expansion between DLBand HC.

4. Discussion

Previous longitudinal studies in DLB have focused on theassessment of global brain measures such as whole brain atrophyrates, yielding somewhat conflicting results. O’Brien et al. (2001)found no significant differences in whole brain atrophy ratesbetween AD and DLB. In contrast, another study with pathologicconfirmation of diagnosis revealed significantly greater globalatrophy rates in AD compared with DLB (Whitwell et al., 2007). Toour knowledge, this is the first study to evaluate the topographicdifferences in the progression of cortical thinning between DLB andAD. The main findings are as follows: (1) DLB and AD are charac-terized by distinct spatial and temporal patterns of cortical thin-ning. Consistent with our hypothesis, the temporal lobe showedsignificantly greater cortical thinning in AD compared with DLBover the follow-up period; (2) regional cortical thinning over timewas correlated with cognitive decline in both AD and DLB groups;and (3) significantly greater loss of hippocampal volume and lateralventricular expansion over 1 year was also observed in the ADgroup.

First, the present longitudinal findings should be interpreted inlight of the baseline comparison (Watson et al., 2014). Compared

) AD and DLB. Results were corrected using family-wise error correction with Z MonteAge and sex were included as nuisance covariates. The color bar shows the logarithmicy bodies; HC, healthy control subjects; Lh, left hemisphere; Rh, right hemisphere. (Forrsion of this article.)

Fig. 2. Vertex-wise correlations between percent of cortical thinning and longitudinal decline in (A) BVMT total scores in AD, (B) MMSE in DLB, (C) CAMCOG-Expressive Language inDLB, (D) CAMCOG-orientation scores in DLB, (E) UPDRS progression in DLB. Results were corrected using family-wise error correction with Z Monte Carlo simulation (10,000)iterations and thresholded at a corrected p-value of 0.01 (Z ¼ 2.0). The color bar shows the logarithmic scale of p values (�log10). Abbreviations: AD, Alzheimer’s disease; BVMT, BriefVisuospatial Memory Test; CAMCOG, Cambridge Cognitive Examination; DLB, dementia with Lewy bodies; Lh, left hemisphere; MMSE, Mini-Mental State Examination; Rh, righthemisphere; UPDRS, Unified Parkinson’s Disease Rating Scale. (For interpretation of the references to color in this figure, the reader is referred to the Web version of this article.)

E. Mak et al. / Neurobiology of Aging xxx (2015) 1e8 5

with similarly aged HC, we have previously reported that ADwas characterized by cortical thinning in the temporoparietalcortices extending into the frontal lobes, whereas amilder degree ofcortical thinning in the parietal regions was evident in DLB.Furthermore, cortical thickness of the left temporal lobe was rela-tively preserved in DLB compared with AD at baseline. As such, it isnoteworthy that our present longitudinal study has revealed asimilar spatial pattern of accelerated thinning in the cortical regionsthat were already thinner in AD compared with HC and DLB atbaseline.

At present, the longitudinal progression of cortical thinn-ing in DLB is relatively unknown. Moreover, the cellularmechanisms through which alpha-synuclein pathologydthecharacteristic hallmark of Lewy body diseasedcontributes toneurodegeneration remains poorly understood (Lashuel et al.,2013). Increasing in vitro evidence also suggests that alpha-syunclein is not a direct causative factor of neurodegeneration.

Table 3Comparisons of longitudinal atrophy in subcortical structures and lateral ventricle expan

Subcortical structures and lateral ventricle Percentage of changea

HC (%) DLB (%)

Thalamus �0.87 �2.01Caudate �1.47 �3.77Putamen �0.39 �0.30Pallidum �0.04 �0.58Hippocampus �1.70 �2.51Amygdala �2.41 �6.25Accumbens �0.33 �1.00Lateral ventricle þ4.29 þ4.70

Key: AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; HC, healthy control suba Percentage of change in volumes between baseline and follow-up, measured accordb Group comparisons were performed with analysis of covariance, correcting for age, ge

pairwise comparisons.c Significant difference at standard threshold of p < 0.05 without correction for multid Significant difference between groups after Bonferroni correction for multiple comp

Rather, it triggers a series of secondary molecular processes thateventually leads to neuroinflammation, disruption of neurotrans-mitters, and eventually cell loss (Lashuel et al., 2013; Wolozin andBehl, 2000). Consistent with this view, we found no differences inthe rates of regional cortical thinning between DLB and HC over 12months. Although it is possible that our negative finding mightrepresent a type II error because of the relatively small sample sizeof DLB (n ¼ 13) and short duration of follow-up (1 year), corrob-orative evidence have come from previous studies. A larger studyhas found similar global and regional brain atrophy rates inpathologically confirmed DLB (n ¼ 20) and HC (n ¼ 15) subjectsover a long follow-up period of 2 years (Nedelska et al., 2014). Inaddition, using a boundary shift integral method, Whitwell et al.(2007) also reported minimal global atrophy rates in DLB (n ¼9) compared with HC (n ¼ 25). Similar patterns of atrophyrates have also been reported in subjects with Parkinson’sdisease (PD), another Lewy body disease (Burton et al., 2005;

sion between groups

Group comparisons of longitudinal subcortical atrophyb

AD (%) AD versus HC DLB versus HC AD versus DLB

�2.41 0.001c 0.06 0.82�3.20 0.23 0.21 0.93�0.82 0.80 0.99 0.820.20 0.97 0.52 0.45

�5.76 <0.001d 0.90 0.006d

�4.80 0.17 0.11 0.84�2.05 0.87 0.94 0.76þ8.91 <0.001d 0.990 0.008c

jects.ing to baseline.nder, and the average total intracranial volume, followed by post hoc Tukey-Kramer

ple comparisons.arisons.

Fig. 3. Longitudinal atrophy in subcortical structures and lateral ventricle expansion.* indicates significant difference at standard threshold of p < 0.05 without correctionfor multiple comparisons. ** indicates significant difference between groups afterBonferroni correction for multiple comparisons. Abbreviations: AD, Alzheimer’s dis-ease; DLB, dementia with Lewy bodies; HC, healthy control subjects.

E. Mak et al. / Neurobiology of Aging xxx (2015) 1e86

Paviour et al., 2006). These convergent findings, despite method-ological differences and sampling (clinical and autopsy confirma-tion), support the view that alpha-synuclein pathologyda majorconstituent of Lewy bodiesdhas limited direct involvement incerebral atrophy. This notion is also consistent with evidencedemonstrating a strong correlation between hippocampal atrophyand b-amyloid plaques and neurofibrillary tangles, but not synu-clein pathology (Burton et al., 2009).

Compared with AD, DLB was characterized by a significantlyslower rate of temporal thinning compared with AD. It is wellestablished that the relative preservation of the medial temporallobe in DLB compared with AD is recognized as the mostconsistent structural MRI finding at the cross-sectional level(Mak et al., 2014) and is in keeping with the different neuro-psychological profiles of both groups. Considered with ourbaseline observation of reduced temporal thickness in AD(Watson et al., 2014), the present findings extend the literatureby elucidating the differential trajectories of temporal thinning inboth conditions over time, thereby validating the inclusion ofmedial temporal lobe preservation as a supportive biomarker forthe clinical diagnosis of DLB (McKeith et al., 2005). Although thediagnostic value of [(123)I]N-omega-fluoropropyl-2beta-carbo-methoxy-3beta-{4-iodophenyl}nortropane (FP-CIT) for DLB hasbeen established to be the “gold standard” in the clinical com-munity (O’Brien et al., 2004), there are clinical benefits to begained with multimodal imaging (i.e., integrating single-photonemission computed tomography and MRI in conjunction). Interms of improving accuracy in differential diagnosis, MRI striatalvolumetric data have been combined with occipital perfusionsingle-photon emission computed tomography to distinguishsubjects with mild DLB from subjects with mild AD with a highdegree of sensitivity and specificity (Goto et al., 2010).

The clinical implications of cortical thinning in DLB are stillpoorly understood. Our correlational analyses of the UPDRS changescores among the DLB subjects revealed a significant associationbetween increased thinning in the superior parietal cortex andgreater motor deterioration. Our findings are in accord with recentvoxel-based morphometry studies demonstrating significant atro-phy of the parietal cortex in PD subjects, presenting with freezing ofgait compared with PD subjects without freezing symptoms(Herman et al., 2014; Rubino et al., 2014). In addition, white matter

hyperintensities in the parietal lobe have been linked to impairedbalance and postural support (Murray et al., 2010). Taken together,these findings fit within the framework that the superior parietallobe is part of the motor system involved in sensorimotorintegration.

The frontal lobe was also involved with cognitive declinein the DLB group. Increased thinning in the superior frontalregions was associated with greater decline in MMSE, an indexof global cognition. In addition, increased thinning in the leftrostral middle frontal regions was correlated with both theorientation and language components of the CAMCOG assess-ment. Similarly, reductions in prefrontal volumes have beencorrelated with attentional deficits (Sanchez-Castaneda et al.,2009). Despite the small sample size in our study, the potentialof the frontal lobe as a plausible biomarker for cognitive impair-ment in DLB should be established further in a larger cohort ofDLB subjects.

Increased cortical thinning over 1 year in AD relative to HC wasfound in the temporoparietal areas extending to the frontal regions.Our results are thus, in agreement with earlier studies demon-strating that AD is associated with progressive loss of whole-brainvolumes, particularly in the medial temporal structures (O’Brienet al., 2001). Increased rates of cortical thinning were also foundin the precuneus and the isthmus of the cingulate gyrus. Bothstructures are involved in the default mode network, which hasbeen found to be impaired in AD (Greicius et al., 2004). Indeed, theprecuneus has been implicated in episodic memory (Krause et al.,1999), whereas the posterior cingulate projects strongly to theentorhinal and parahippocampal cortices, both of which are amongthe earliest sites of pathologic changes in AD (Van Hoesen et al.,1991).

Consistent with the differential patterns of progressive corticalthinning in AD and DLB, our longitudinal analyses of subcorticalchanges also revealed significantly faster atrophy in the AD group,particularly in the hippocampus and the thalamus albeit at trendlevel. The finding of increased ventricular expansion in ADcompared with HC and DLB also agrees with previous studies(Thompson et al., 2004).

The major strengths of the study include the comprehensiveneuropsychological assessment and a well-characterized group ofprobable DLB and AD patients. In addition, all the groups werematched for age, gender, and educational level. The longitudinaldesign, a rarity in the DLB imaging literature, allowed us to addressunanswered questions related to the progression and clinical im-plications of cortical thinning in Lewy body dementia. Some po-tential limitations of this study include the lack of neuropathologicverification of AD and DLB, as subject groups were based onclinical diagnosis, although this is an inherent limitation of allantemortem imaging studies. Furthermore, we have previouslydemonstrated good agreement between clinical and pathologicdiagnosis using the consensus clinical diagnostic method adoptedhere (McKeith et al., 2000). Attrition of subjects is also a commondrawback in longitudinal studies. Less than half (n ¼ 14) of theoriginally recruited DLB subjects (n ¼ 35) returned for a follow-upassessment because of disease progression including 9 deaths.However, they did not differ from those who were unable tocomplete the 12-month assessment (n ¼ 21) in age or measures ofglobal cognition, neuropsychiatric features, or motor parkinsonism(Table 2). Finally, to minimize the number of comparisons betweenthe DLB, AD, and HC groups, we have summed the left and righthemispheric measures of each subcortical structure. Althoughthere is no evidence to indicate systematic laterality of subcorticalchanges in AD and DLB, our combined volumes for each structuremight have resulted in a loss of potential information aboutasymmetrical disease-related changes.

E. Mak et al. / Neurobiology of Aging xxx (2015) 1e8 7

5. Conclusion

In accordance with our hypothesis, faster thinning over 1 yearwas found in the temporal lobe in AD relative to DLB. Besidesvalidating the inclusion of the medial temporal lobe as a sup-portive biomarker in the revised diagnostic criteria for DLB, ourfindings also highlight the clinical utility of longitudinal corticalthinning as a complementary imaging marker to differentiate DLBfrom AD. Greater cortical thinning could exert deleterious effectson global cognitive decline and was associated with increasingmotor severity in DLB. However, our finding of similar ratesof cortical thinning in DLB and HC underscores the ongoingneed to develop other surrogate biomarkers of disease progres-sion in DLB.

Disclosure statement

John O’Brien has acted as a consultant for GE Healthcare, Lilly,TauRx, and Cytox. All other authors report no conflict of interests.

Acknowledgements

This work was supported by the Sir Jules Thorn Charitable Trust(Grant number 05/JTA), the NIHR Biomedical Research Unit in De-mentia and the Biomedical Research Centre awarded to CambridgeUniversity Hospitals NHS Foundation Trust and the University ofCambridge, and the NIHR Biomedical Research Unit in Dementiaand the Biomedical Research Centre awarded to Newcastle uponTyne Hospitals NHS Foundation Trust and the Newcastle University.Elijah Mak was in receipt of a Gates Cambridge PhD studentship.Elijah Mak formulated the research question, performed the sta-tistical analyses, interpreted the results, and wrote the article. Li Suand GuyWilliams assistedwith the interpretation of the results andprovided comments and additional suggestions for revisions of thedraft. Rosie Watson recruited and assessed study participants,assisted with the interpretation of the results, and reviewed thearticle. Michael Firbank designed the imaging protocol, assistedwith the interpretation of the results, and reviewed the article.Andrew Blamire obtained funding for the project, designed theimaging protocol, undertook routine quality assurance on the MRsystem, assisted with the interpretation of the results, and reviewedthe article. John O’Brien obtained funding for the project, designedthe imaging protocol, assisted with recruitment of study partici-pants, assisted with the interpretation of the results, and reviewedthe article. All authors approved the final article.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.038.

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