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Do Alzheimer’s disease (AD) and subcortical ischemic vasculardementia (SIVD) progress differently?

Yun Jeong Hong a, Bora Yoon b, Yong S. Shim c, Il-Woo Han a, Seol-Heui Han d,Kee Hyung Park e, Seong Hye Choi f, Bon D. Ku g, Dong Won Yang c,*a Department of Neurology, Yong-In Hyoja Geriatric Hospital, 33 Sangha-dong, Giheung-gu, Yongin 446-769, Republic of Koreab Department of Neurology, Konyang University College of Medicine, 685 Gawuwon-dong, Seo-gu, Daejeon 302-718, Republic of Koreac Department of Neurology, Catholic University of Korea, The College of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701, Republic of Koread Department of Neurology, Konkuk University School of Medicine, Hwayang-dong, Gwangjin-gu, Seoul 143-729, Republic of Koreae Department of Neurology, Gachon University Gil Medical Center, Guwol 1-dong, Namdong-gu, Incheon 405-760, Republic of Koreaf Department of Neurology, Inha University School of Medicine, Sinheung-dong 3 ga, Jung-gu, Incheon 400-711, Republic of Koreag Department of Neurology, Myongji Hospital, Kwandong University College of Medicine, Hwajeong 1-dong, Deogyang-gu, Goyang 412-826, Republic of Korea

A R T I C L E I N F O

Article history:

Received 13 August 2013

Received in revised form 12 November 2013

Accepted 14 November 2013

Available online xxx

Keywords:

AD

Cognitive neuropsychology

Disease progression

SVD

SIVD

A B S T R A C T

Our study aimed to compare cognitive status and declines in AD with/without small vessel disease (SVD)

and SIVD at baseline and 1-year follow-up. Patients with Alzheimer’s disease without small vessel

disease (AD(�)SVD) (n = 148), Alzheimer’s disease with small vessel disease (AD(+)SVD) (n = 94)

and SIVD (n = 60) were recruited from database of multiple centers in Korea. Basic demographics and

detailed neuropsychological results were compared. AD, regardless of SVD, showed worse memory

and better executive function than SIVD at baseline. Mini-Mental State Examination scores and visual

memory function declined more in AD than those in SIVD whereas Barthel Activities of Daily Living

(B-ADL) scores declined more in SIVD. AD showed different patterns of cognitive impairment compared

with SIVD. After 1 year, AD showed more rapid cognitive decline in some domains. Further investigations

with longer follow-up duration may be needed to confirm the cumulative effects of SVD in AD and

different patterns of decline between AD and SIVD.

� 2013 Published by Elsevier Ireland Ltd.

Contents lists available at ScienceDirect

Archives of Gerontology and Geriatrics

jo ur n al ho mep ag e: www .e lsev ier . c om / lo cate /ar c hg er

1. Introduction

SIVD is one of the most common subtypes of vascular dementiaand is characterized by lacunar infarctions and severe white matterchanges (Lee et al., 2011; Roman, Erkinjuntti, Wallin, Pantoni, &Chui, 2002). Vascular dementia is a heterogeneous disease thatincludes various pathophysiological mechanisms (Sorrentino,Migliaccio, & Bonavita, 2008), whereas SIVD is a clinically morehomogenous disease (Roman et al., 2002).

Patients with dementia and their caregivers are mostlyconcerned about disease progression. Many studies have reportedon the cognitive and functional progression of AD; however, theprogression of SIVD has been less studied. Only a few studies havecompared rates of progression between AD and vascular dementia;some have found that the rate of decline is faster in AD than that invascular dementia (Aguero-Torres, Fratiglioni, Guo, Viitanen, &Winblad, 1998; Nyenhuis, Gorelick, Freels, & Garron, 2002),whereas others have found that the rate of decline in vascular

* Corresponding author. Tel.: +82 2 2258 6077; fax: +82 2 599 9686.

E-mail address: neuroman@catholic.ac.kr (D.W. Yang).

Please cite this article in press as: Hong, Y.J., et al., Do Alzheimer’s

progress differently? Arch. Gerontol. Geriatr. (2013), http://dx.doi.or

0167-4943/$ – see front matter � 2013 Published by Elsevier Ireland Ltd.

http://dx.doi.org/10.1016/j.archger.2013.11.005

dementia is faster (Cohen-Mansfield, Gruber-Baldini, Culpepper, &Werner, 1996) than or comparable (Small, Viitanen, Winblad, &Backman, 1997) to that in AD. These inconsistent results may beattributed to the variety of cognitive measurement tools used,small sample sizes, the heterogeneity of vascular dementia(Nyenhuis et al., 2002) and coexistent AD.

SIVD does not follow the general patterns of disease course invascular dementia, namely abrupt onset and stepwise progressivepatterns. The presence of SVD may also affect the progression ofAD. Thus, it is worth comparing the effects of SVD and Alzheimer’spathology in the progression of dementia. No study has comparedthe rate and pattern of decline among pure AD(�)SVD, AD(+)SVD,and SIVD.

We predicted that AD and SIVD would show different patternsof cognitive and functional status at baseline and they wouldprogress differently according to the pathophysiology of dementia.We also predicted that presence of SVD may accelerate theprogression of AD. Hence, we investigated baseline and 1-yearlongitudinal follow-up data from the Clinical Research Centers forDementia of South Korea (CREDOS) to compare the rates ofcognitive and functional declines in patients with AD(�)SVD,AD(+)SVD, and SIVD.

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2. Materials and methods

2.1. Subjects

Data were collected in 31 dementia clinics from university-affiliated hospitals in South Korea from November 2005 to October2010. This research was performed as part of a nationwidemulticenter study of dementia called the CREDOS study. All of thepatients visited dementia clinics for dementia work up andunderwent evaluations for dementia diagnosis. The CREDOS studyrecruited consecutive patients in categories of normal control,subjective memory impairment (SMI), mild cognitive impairment(MCI), vascular mild cognitive impairment (VMCI), AD, or SIVD tounderstand the characteristics of patients with dementia. Allpatients were assessed using the Seoul NeuropsychologicalScreening Battery (SNSB) as a formal comprehensive neuropsy-chological test (Kang & Na, 2003), caregiver questionnaires, B-ADLand Seoul Instrumental Activities of Daily Living (S-IADL) scales,brain magnetic resonance imaging (MRI), and blood tests includinga complete blood count, blood chemistry values, vitamin B12/folatevalues, syphilis serology, and thyroid function tests at baseline.Genomic DNA was extracted from venous blood for apolipoproteinepsilon (APOE) genotyping, if patients and caregivers agreed.Neurologists of each center diagnosed clinically after theyexamined the patients and reviewed all of the findings. All studypatients underwent a comprehensive neuropsychological testsbattery using the SNSB, caregiver questionnaires, and physical/neurological examinations at subsequent annual examinations.Only subjects with 1 year (�3 months) follow-up data were includedin this study.

Patients with dementia that satisfied the criteria for probableAD issued by the National Institute of Neurologic and Communi-cative Disorders and Stroke and the AD and Related DisordersAssociation (NINCDS-ADRDA) were considered to have AD(McKhann et al., 1984). AD patients with lacunar infarction ormoderate to severe white matter hyperintensity (WMH) wereconsidered to have AD(+)SVD. AD patients with mild WMH and noinfarction were considered to have AD(�)SVD. SIVD patients metthe criteria for subcortical vascular dementia proposed byErkinjuntti et al. (2000).

Exclusion criteria were those with a history of significanthearing or visual impairment that rendered participation in theinterview difficult, history of neurological disorders (e.g.,Parkinson’s disease or active epilepsy), psychiatric illnesses(e.g., schizophrenia, mental retardation or bipolar disorder) otherthan dementia, and a history of significant alcohol or othersubstance abuse. Patients with abnormal lab findings (abnormalthyroid function, low vitamin B12/folate levels, or positivesyphilis serology) were excluded because these conditions cancause cognitive impairment. We also excluded patients withsevere dementia, clinical dementia rating (CDR) of 3, to removethe floor effect.

This study was approved by the Institutional Review Board ofeach participating hospital, and written informed consent wasobtained at the enrollment of the CREDOS cohort after providing acomplete description of the study to the subjects and theircaregivers.

2.2. History of comorbid conditions and neurological examinations

Comorbidities at baseline were examined with a semi-structured questionnaire that identified five categories of illnessrelated to vascular disease including diabetes mellitus, hyper-tension, hyperlipidemia, heart disease, and stroke. Caregivers ofpatients with dementia who lived with or met with patientsmore than three times per week answered the questions.

Please cite this article in press as: Hong, Y.J., et al., Do Alzheimer’s

progress differently? Arch. Gerontol. Geriatr. (2013), http://dx.doi.o

Neurologists conducted neurological examinations at eachcenter to identify neurological symptoms and signs for thediagnosis of SIVD.

2.3. Brain MRI and measurement of WMH and lacunar infarct

The MRI scans included trans-axial T2- and T1-weighted,gradient-echo, fluid-attenuated inversion recovery (FLAIR), andcoronal T1-weighted images. The neurologist at each centermeasured the severity of WMH using visual rating of axial FLAIRimages. The longest diameter of WMH around the periventriculararea (capping and banding) and the deep white matter area(separated from the periventricular area by normal-appearingwhite matter) were evaluated separately. The periventricularWMH was rated as P1 (<5 mm), P2 (�5 mm, <10 mm), or P3(�10 mm). The deep WMH was rated as D1 (<10 mm), D2(�10 mm, <25 mm), or D3 (�25 mm). The results werecombined to rank the severity of WMH as minimal, moderate,or severe. Combinations of D1 and P1 (D1P1) and of D1 and P2(D1P2) were placed in the minimal WMH group. Patients withD3P3 were placed in the severe WMH group. Other possiblecombinations (D2P1, D3P1, D2P2, D3P2, D1P3, and D2P3) wereclassified as moderate. The inter-rater reliability for theperiventricular hyperintensity and deep WMH was good(intraclass correlation coefficient of 0.726–0.905). Lacunarinfarctions were counted by a neurologist using FLAIR T2- andT1-weighted images. Lacunar infarctions were defined by thefollowing criteria: cavitated lesion with surrounding gliosis, 3–15-mm diameter, hyperintensity on T2-weighted image, andhypointensity on T1-weighted image.

2.4. Neuropsychological test battery

All patients participated in formal neuropsychological testingincluding the Korean version of the Mini-Mental State Examination(K-MMSE) (Han et al., 2008), CDR scales, measures of physicalactivities or instrumental activities of daily living (B-ADL, S-IADL),and the SNSB, which is a detailed neuropsychological battery thatcontains tests for attention (forward/backward digit span),language (repetition, naming, reading, and writing), praxis(ideomotor and buccofacial), visuospatial function (Rey ComplexFigure Test (RCFT), verbal and visual memory function (immediateand delayed recall, recognition subtest of the Seoul Verbal LearningTest (SVLT and RCFT)), and frontal executive function (contrastingprogram, go-no-go, Controlled Oral Word Association Test(COWAT), and Stroop test). These tests were administered bytrained neuropsychological technicians or neuropsychologists.Age-, gender-, and education-specific norms based on 447 normalsubjects were used to interpret the SNSB results. Scores below the16th percentile, which is comparable to �1 standard deviation ofthe norm for age and education-matched normal subjects, weredefined as abnormal. All neuropsychological tests and caregiverquestionnaires were administered again during subsequent annualexaminations.

2.5. Statistical analysis

Comparisons of the APOE e4 allelic frequencies, comorbidity,and gender distributions were performed using Pearson’s chi-square analysis. Baseline mean age, educational level, symptomduration and baseline neuropsychological test results werecompared using non-parametric Kruskal–Wallis method. Scoredifferences between baseline and the 1-year follow-upwere compared using repeated measures ANOVA. We used SPSSversion 16.0 (Chicago, IL, USA) for the statistical analysis. A p-value<0.05 was considered significant.

disease (AD) and subcortical ischemic vascular dementia (SIVD)rg/10.1016/j.archger.2013.11.005

Table 1Basic demographic information and summary of cognitive measures.

1. AD(�)SVD (n = 148) 2. AD(+)SVD (n = 94) 3. SIVD (n = 60) p value Post hoc analysis

Age (years) 73.6 � 5.01 75.2 � 5.67 73.7 � 6.73 0.078 1 = 2 = 3

Female (%) 64.3% 67.0% 55.8% 0.388 1 = 2 = 3

Education (years) 8.5 � 5.33 8.3 � 4.92 8.4 � 4.90 0.909 1 = 2 = 3

APOE4 allele 57.7% (45/78) 53.4% (31/58) 30.6% (11/36) 0.023 1 = 2 > 3

Disease duration (years) 2.5 � 8.57 2.0 � 8.98 3.8 � 10.34 0.367 1 = 2 = 3

Diabetes mellitus 22.9% 13.4% 21.2% 0.182 1 = 2 = 3

Hypertension 42.9% 54.6% 84.6% <0.001 3 > 1 = 2

Hyperlipidemia 22.9% 17.5% 17.3% 0.518 1 = 2 = 3

Cardiac disease 12.9% 17.5% 21.2% 0.327 1 = 2 = 3

Stroke 3.6% 11.3% 25.0% <0.001 3 > 1 = 2

K-MMSE score 20.1 � 4.05 20.4 � 4.72 20.8 � 4.10 0.519 1 = 2 = 3

CDR score 0.85 � 0.478 0.90 � 0.493 0.80 � 0.457 0.455 1 = 2 = 3

CDR-SOB 4.90 � 2.739 5.32 � 3.090 4.85 � 2.363 0.824 1 = 2 = 3

GDS 12.7 � 7.50 14.1 � 7.75 17.1 � 7.07 0.002 3 > 1 = 2

Mean � S.D.

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3. Results

Totally 282 patients with AD or SIVD underwent 1 year (�3months) of follow-up examinations and were included in this study.Total follow-up duration ranged from 9 to 39 months, and follow-upvisits ranged from 1 to 3 times per patient. Basic demographic dataand neuropsychological test results at baseline between patients withAD and those with SIVD are listed in Tables 1 and 2. The three groupsshowed similar demographics except for APOE4 allele frequency.Patients with SIVD reported hypertension more often and morefrequently had a history of stroke compared with patients with ADwith/without SVD. Comparisons of neuropsychological tests showedsimilar results for the cognitive summary measures (K-MMSE, CDR,and CDR sum of boxes (CDR-SOB)) and one functional measure, S-IADL, in the three groups. All of the neuropsychological tests resultswere similar between AD(�)SVD and AD(+)SVD at baseline. However,patients with SIVD had lower B-ADL scores (p = 0.001) and higher

Table 2Baseline neuropsychological results.

1. AD(�)SVD (n =

Functional independence

S-IADL 13.8 � 8.74

B-ADL 19.8 � 0.85

Attention (digit span test)

Forward digit span 4.9 � 1.39

Backward digit span 2.7 � 1.19

Language (K-BNT – Korean Version of the Boston Naming Test) 31.8 � 10.43

Visuospatial (RCFT) 24.3 � 10.56

SVLT

immediate recall 11.2 � 4.23

delayed recall 0.5 � 1.15

Recognition 62.7 � 11.47

RCFT

immediate recall 3.6 � 3.14

delayed recall 2.8 � 3.50

Recognition 64.2 � 10.22

Frontal executive function

COWAT animal 9.1 � 3.45

COWAT market 8.8 � 4.35

COWAT phonemic 14.2 � 8.72

Stroop color-reading correct number 48.1 � 24.39

Stroop color-reading time/item (second) 2.5 � 1.23

Go-No-Go test 12.0 � 7.11

Contrasting program 14.8 � 7.64

Higher scores mean better function, except for the S-IADL. Mean � S.D.

Please cite this article in press as: Hong, Y.J., et al., Do Alzheimer’s

progress differently? Arch. Gerontol. Geriatr. (2013), http://dx.doi.or

geriatric depression scale (GDS) scores (p = 0.002) compared withthose in the two AD groups. The verbal memory scores (mean SVLTdelayed recall and recognition scores) were lower in patients with ADwith/without SVD compared with SIVD, whereas visuospatialfunction (RCFT copy score), mean COWAT scores (animal, market,and phonemic tests) and Stroop test correct numbers were lower inpatients with SIVD.

Mean scores changes after 1 year in each group are shown inTable 3. The K-MMSE score decline was 2.2 � 3.23 in patients withAD(+)SVD during the 1 year. This was larger than the changes amongAD patients without SVD and those with SIVD (p = 0.027). The threegroups showed similar declines on the CDR, CDR-SOB, GDS, and S-IADL and on all of the SNSB test domains except the visual memoryfunction (RCFT delayed recall). Visual memory delayed recall scoresdeclined more in AD with/without SVD compared with those in SIVD.The B-ADL score declined more in patients with SIVD than it did inpatients with AD with/without SVD (p < 0.001).

148) 2. AD(+)SVD (n = 94) 3. SIVD (n = 60) p value Post hoc

16.0 � 9.42 15.1 � 9.73 0.292 1 = 2 = 3

19.3 � 2.10 18.7 � 2.85 0.005 2 = 1 > 3

5.0 � 1.31 5.1 � 1.64 0.505 1 = 2 = 3

2.7 � 1.03 2.6 � 1.24 0.714 1 = 2 = 3

31.2 � 10.82 30.6 � 10.59 0.795 1 = 2 = 3

22.1 � 11.00 20.9 � 10.59 0.036 2 = 1 > 3 = 2

10.9 � 4.23 10.7 � 3.57 0.323 1 = 2 = 3

0.8 � 1.60 1.3 � 2.00 0.001 3 > 1 = 2

64.7 � 11.68 70.0 � 13.72 0.003 3 > 1 = 2

3.8 � 4.48 3.4 � 4.05 0.350 1 = 2 = 3

2.8 � 3.91 3.1 � 3.79 0.953 1 = 2 = 3

66.8 � 11.26 67.5 � 11.07 0.117 1 = 2 = 3

8.6 � 3.30 7.8 � 3.15 0.048 1 = 2 > 3

7.8 � 4.18 6.8 � 3.86 0.015 1 = 2 > 3

12.1 � 8.56 8.0 � 8.00 <0.001 1 = 2 > 3

43.0 � 25.44 36.8 � 26.23 0.040 1 = 2 > 3

2.8 � 1.48 3.00 � 1.43 0.046 1 > 3 = 2

13.3 � 6.56 11.4 � 7.31 0.194 1 = 2 = 3

14.9 � 7.16 14.9 � 7.55 0.892 1 = 2 = 3

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Table 3Comparisons of cognitive and functional declines after 1 year among the groups.

1. AD(�)SVD (n = 148) 2. AD(+)SVD (n = 94) 3. SIVD (n = 60) p value

Cognitive and function summary measures

K-MMSE score 1.2 � 2.89 2.2 � 3.23 1.0 � 3.37 0.037

CDR �0.1 � 0.43 �0.2 � 0.38 �0.3 � 0.52 0.086

CDR-SOB �1.1 � 2.13 �1.4 � 1.99 �1.4 � 2.99 0.545

S-IADL �4.1 � 8.27 �3.2 � 8.17 �3.2 � 8.83 0.504

B-ADL 0.3 � 1.10 0.6 � 1.55 1.5 � 3.49 <0.001

GDS score 1.1 � 5.84 0.6 � 6.00 �0.6 � 6.17 0.280

Attention (digit span test)

Forward digit span 0.2 � 1.20 0.1 � 1.15 0.2 � 1.28 0.899

Backward digit span 0.1 � 1.05 0.2 � 0.99 0.0 � 0.88 0.491

Language (K-BNT) 2.4 � 5.64 3.1 � 5.69 1.8 � 4.54 0.113

Visuospatial (RCFT) 0.8 � 6.94 1.8 � 7.84 2.4 � 6.84 0.598

SVLT

immediate recall 0.4 � 3.49 0.6 � 3.82 0.6 � 3.38 0.673

delayed recall 0.1 � 1.22 0.1 � 1.07 0.1 � 1.60 0.601

recognition 0.9 � 12.63 1.0 � 11.67 2.4 � 10.30 0.440

RCFT

immediate recall 0.2 � 2.96 0.4 � 3.64 0.0 � 3.10 0.935

delayed recall 1.1 � 2.53 0.9 � 3.34 0.2 � 2.57 0.047

recognition �0.1 � 10.16 4.1 � 12.22 2.4 � 14.01 0.056

Frontal executive function

COWAT animal 0.5 � 3.16 0.7 � 3.73 0.6 � 3.00 0.948

COWAT market 0.9 � 4.16 0.4 � 3.44 1.0 � 4.11 0.649

COWAT phonemic 0.6 � 5.99 0.1 � 6.64 1.0 � 6.10 0.934

Stroop color-reading correct number 2.7 � 17.92 4.2 � 18.40 1.7 � 18.14 0.103

Stroop color-reading time/item �0.3 � 2.08 �0.4 � 1.62 �1.2 � 4.82 0.162

Go-No-Go test �0.5 � 7.27 0.3 � 7.87 �0.1 � 8.41 0.716

Contrasting program �0.2 � 6.61 �0.2 � 7.71 1.0 � 7.48 0.231

One year change, (baseline score)-(follow up score). Higher score means more decline after one year except for the S-IADL and GDS. Mean � S.D.

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4. Discussion

We compared cognitive and functional declines in clinicallydiagnosed patients with AD(�)SVD, those with AD and SVD, andthose with SIVD at baseline and after 1 year using comprehensiveneuropsychological tests, and we obtained a few interestingfindings.

AD(�)SVD was not significantly different from AD(+)SVD atbaseline regardless of the presence of SVD. Baseline characteristicssuch as APOE4 allele frequency and incidences of hypertension orstroke were different between SIVD and the two AD groups. Thesefindings are consistent with previous results based on the CRCDdatabase that reported higher APOE4 allele frequency in AD andhigher incidences of hypertension and stroke in SIVD (Hong et al.,2011). APOE4 is one of the most popular risk factors for AD. On theother hand, both hypertension and stroke are risk factors forlacunar infarction and WMH, and these may explain thedifferences between patients with AD and those with SIVD.

The SVLT scores representing verbal memory function wereworse in patients with AD, whereas scores on the COWAT andStroop test, which represent frontal executive function, wereworse in patients with SIVD. Verbal memory function reflectstemporal lobe function, and these results indicate greaterprogressive pathological degeneration in the temporal lobes ofpatients with AD. The frontal lobe dysfunctions in SIVD may be dueto frontal subcortical disruption and interruption of long associa-tion fibers, which are important for cognition (Chui, 2007; Romanet al., 2002). Temporal lobe function is mainly impaired in AD,whereas frontal lobe function is mainly impaired in SIVD (Graham,Emery, & Hodges, 2004; Traykov et al., 2002). Patients with AD andSIVD showed different patterns of cognitive dysfunction inbaseline neuropsychological tests, although their cognitive sum-mary measures such as K-MMSE, CDR, and CDR-SOB were notdifferent. The two groups of AD showed similar patterns ofcognitive dysfunction in baseline regardless of the presence of SVD.

Please cite this article in press as: Hong, Y.J., et al., Do Alzheimer’s

progress differently? Arch. Gerontol. Geriatr. (2013), http://dx.doi.o

Patients with SIVD, similar with vascular dementia, were moredepressed and physically dependent than patients with AD.Previous studies showed that vascular dementia causes moredepressed mood (Castilla-Puentes & Habeych, 2010; Newman,1999), and greater physical dependency (Gure, Kabeto, Plassman,Piette, & Langa, 2010). Both lacunar infarction and severe WMH areassociated with depression (O‘Brien et al., 2006; White et al., 2011),so-called vascular depression. Moreover, depressed mood may beassociated with poor physical function (Vital et al., 2012). We alsodemonstrated that physical dependency in SIVD became worseafter 1 year compared with that in the AD groups. SVD that isassociated with poor physical functioning due to neurologicalsymptoms and signs (Moon et al., 2011) may progress more rapidlyin SIVD.

One of the important findings of this study is that MMSEscores revealed greater decline in patients with AD(+)SVDcompared with those in the other two groups (AD(�)SVD andSIVD). RCFT delayed recall, which represents visual memoryfunction, declined more in patients with AD compared with thatin SIVD. Additionally, RCFT recognition also showed marginaltrend of more decline (p = 0.056) in patients with AD(+)SVD.These results are partially consistent with previous studies thatreported more rapid cognitive declines in AD than in vasculardementia (Aguero-Torres et al., 1998; Nyenhuis et al., 2002),however, our study is different from previous studies in that weonly included patients with SIVD, a more homogenous subtype ofvascular dementia, and we divided AD into two groups accordingto presence of SVD on MRI. Our study showed more cognitivedecline in patients with AD with/without SVD compared withthat in patients with SIVD in some domains like general cognitivesummary measures (MMSE) and visual memory function.However, most neuropsychological tests results after 1 yearshowed similar decline between AD and SIVD. Moreover,physical dependency is worse in SIVD after 1 year. Thesefindings might suggest that attempts to delay the progression of

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SIVD are also needed. Controlling the vascular risk factorsassociated with SIVD may reduce the progression of SIVD.

The current study had several limitations. First, the diagnosiswas based on clinical findings and structural brain imaging ratherthan on confirmatory pathological data. It is possible that some ofthe patients with SIVD had concomitant AD pathology and viceversa. Recent articles suggested that many patients with clinicallydiagnosed SIVD have coexistent AD pathology. Moreover, potentialselection bias due to choice of diagnostic criteria of AD and SIVDmight exist. Combination of vascular pathology and AD isfrequently termed ‘mixed dementia’ or some suggest that vasculardementia, mixed dementia and AD are not separate disease butcontinuous spectrum. Hence, SIVD in our study might be examplesof mixed dementia or AD with prominent vascular pathology.However, Lee et al. reported that 31 of 45 (68.9%) patients withclinically diagnosed SIVD were negative for cortical Pittsburghcompound B (PiB) binding. They showed that SIVD withoutabnormal amyloid deposition was more common than expected(Lee et al., 2011). We attempted to reduce misdiagnoses bycarefully using medical history, physical and neurological exami-nation, neuropsychological tests, brain MRI, and blood tests.Patients without neurological signs/symptoms or lacunar infarc-tions were excluded from the SIVD group to eliminate mixedpathology even though they had severe WMH. The short follow-upduration might be another limitation. Hence, long-term follow-upis needed to characterize clinical and functional progression ofAD(�)SVD, AD(+)SVD, and SIVD. Third, some risk factors that areassociated with dementia progression were insufficientlyaddressed in our study. For example, information about typesand amounts of anti-dementia drugs might be needed to confirmour results. All three groups were taking anti-dementia medica-tions because patients with SIVD and AD can be prescribedacetylcholinesterase inhibitors in Korea.

Despite these limitations, this is believed to be the first well-defined multicenter cohort study to compare progression in ADwith and without SVD and SIVD, based on a relatively large samplesize and comprehensive neuropsychological testing. Moreover, weinvestigated the effects of SVD and Alzheimer’s pathology on theprogression of dementia.

In conclusion, we report different patterns of cognitiveimpairment between AD with/without SVD and SIVD at baseline.In addition, more rapid decline of MMSE scores and visual memoryfunction were shown in patients with AD during 1-year follow-up.SIVD showed more decline in physical function compared withthat of AD. Further investigations with longer follow-up durationand additional data may be needed to confirm the cumulativeeffects of SVD in AD and different patterns of decline between ADand SIVD.

Conflict of interest

None.

Acknowledgments

This study was supported by a grant of the Korea HealthcareTechnology R&D Project, Ministry for Health, Welfare & Family

Please cite this article in press as: Hong, Y.J., et al., Do Alzheimer’s

progress differently? Arch. Gerontol. Geriatr. (2013), http://dx.doi.or

Affairs, Republic of Korea (HI10C2020). The funding source had noinvolvement in the study.

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