Journal of Alzheimer’s Disease xx (20xx) x–xx 1

DOI 10.3233/JAD-160637
IOS Press

1 Face-Name Associative Recognition

2 Deficits in Subjective Cognitive Decline
and Mild Cognitive Impairment

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4 Alexandra Polchera,b,∗ , Ingo Frommanna,b , Alexander Kopparaa,b , Steffen Wolfsgrubera,b ,
5 Frank Jessena,c and Michael Wagnera,b
a German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

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6

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b Department of Psychiatry, University of Bonn, Germany
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c Department of Psychiatry, University of Cologne, Germany

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Accepted 8 December 2016

9 Abstract.
10 Background: There is a need for more sensitive neuropsychological tests to detect subtle cognitive deficits emerging in the
11
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preclinical stage of Alzheimer’s disease (AD). Associative memory is a cognitive function supported by the hippocampus
12 and affected early in the process of AD.
13 Objective: We developed a short computerized face-name-associative-recognition test (FNART) and tested whether it would
14 detect memory impairment in memory-clinic patients with mild cognitive impairment (MCI) and subjective cognitive decline
15 (SCD).
16 Methods: We recruited 61 elderly patients with either SCD (n = 32) or MCI (n = 29) and 28 healthy controls (HC) and
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17 compared performance on FNART, self-reported cognitive deterioration in different domains (ECog-39), and, in a reduced
18 sample (n = 46), performance on the visual paired associates test of the CANTAB battery.
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19 Results: A significant effect of group on FNART test performance in the total sample was found (p < 0.001). Planned contrasts
20 indicated a significantly lower associative memory performance in the SCD (p = 0.001, d = 0.82) and MCI group (p < 0.001,
21 d = 1.54), as compared to HCs, respectively. The CANTAB-PAL discriminated only between HC and MCI, possibly because
22 of reduced statistical power. Adjusted for depression, performance on FNART was significantly related to ECog-39 Memory
23 in SCD patients (p = 0.024) but not in MCI patients.
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24 Conclusions: Associative memory is substantially impaired in memory-clinic patients with SCD and correlates specifically
25 with memory complaints at this putative preclinical stage of AD. Further studies will need to examine the predictive validity
26 of the FNART in SCD patients with regard to longitudinal (i.e., conversion to MCI/AD) and biomarker outcomes.

27 Keywords: Alzheimer’s disease, associative memory, cognition, early detection, hippocampus, mild cognitive impairment,
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28 neuropsychological tests, recognition, subjective cognitive decline

29 INTRODUCTION increased risk for progression to dementia at the pre- 34

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clinical stage of the disease with the aim to target early 35

30 The pathology of Alzheimer’s disease (AD) is intervention and to provide an adequate treatment. 36

31 manifold and occurs years to decades before the first Preclinical AD is considered as the first stage of AD, 37

32 manifestation of cognitive symptoms [1, 2]. Current initially characterized by an asymptomatic accumu- 38

33 research tries to identify and characterize subjects at lation of amyloid. Further progression of the disease 39

∗ Correspondence
is accompanied by neurodegeneration. Finally, at the 40
to: Alexandra Polcher, MSc, Department of
Psychiatry, University of Bonn, Germany, Sigmund-Freud-Straße
transitional stage between preclinical AD and mild 41

25, 53127 Bonn, Germany. Tel.: +49 228 287 16946; Fax: +49 cognitive impairment (MCI) due to AD, subtle cogni- 42

16371; E-mail: Alexandra.Polcher@dzne.de. tive impairments on tests with high sensitivity to AD 43

ISSN 1387-2877/17/$35.00 © 2017 – IOS Press and the authors. All rights reserved
 2 A. Polcher et al. / Associative Recognition in SCD and MCI

44 pathology, and self-experienced cognitive decline complaints [22]. It remains to be determined whether 96

45 may arise [2]. different associative tasks yield similar results or 97

46 Subjective cognitive decline (SCD) may thus rep- whether the type of items to be associated mat- 98

47 resent the first symptomatic manifestation of AD and ters. Face-name association requires the association 99

48 precede MCI [3]. This assumption is supported by of verbal with biologically meaningful visual face 100

49 studies which highlighted SCD as a risk factor for stimuli, which might tap into different brain areas 101

50 future cognitive decline and progression to MCI and than a visual-spatial task with abstract geometric 102

51 AD dementia [4–8]. figures. 103

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52 Several studies have shown that memory clinic Refinement and further validation of tasks with 104

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53 patients with SCD, who were unimpaired in tra- increased sensitivity to changes occurring early in 105

54 ditional neuropsychological tests, exhibit signs of the course of AD will be a valuable enhancement of 106

55 neurodegeneration and dysfunction, attributed to the neuropsychological toolbox for clinical studies. 107

56 putative pathological processes underlying AD, The purpose of the present study was to investigate 108

57 e.g., gray matter atrophy in the hippocampus and the sensitivity of a face-name associative memory test 109

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58 entorhinal cortex [9–12]. Furthermore, a decreased in memory clinic patients with SCD and MCI, and 110

59 activation of the right hippocampus as well as an to examine associations with self-reported cognitive 111

60 increased activation of the right dorsolateral pre- problems in everyday life. Inspired by the similar 112

61 frontal cortex during performance on an associative Face Name Associative Memory Exam (FNAME) 113

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62 memory test has been reported [13]. Furthermore, a [18], we developed a computerized paired-associate 114

63 study including healthy older individuals with SCD recognition test which also requires pairing of faces 115

64 and applying positron emission tomography with and names during learning (FNART; Face-Name 116

65 Pittsburg Compound B (PiB-PET) showed evidence Associative Recognition Test). However, the FNART, 117

66 of brain ␤-amyloidosis in these individuals compared in contrast to the FNAME and other similar tests 118
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67 to healthy controls (HC) without SCD [14]. Sub- [23, 24], does not employ free recall of the name 119

68 tle decline in cognition at the end of the preclinical which was learned to go with a face. Rather, the 120

69 stage of AD is, by definition, difficult to detect with FNART only requires a forced choice about which 121

70 standardized neuropsychological tests [3]. Only few among several presented names belongs to the face 122

71 studies report slight cognitive impairment on estab- shown. This response format is identical to the for- 123

lished [15, 14] or novel [16] cognitive tests in patients mat used in previous functional imaging studies of
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72 124

73 or individuals with SCD. face-name association learning, which have consis- 125
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74 Some recently developed tests exhibit increased tently shown stronger hippocampal activation during 126

75 sensitivity for cognitive deficits in preclinical AD successful learning of face-name associations, which 127

76 and have been associated with AD pathology [17]. were subsequently recognized outside the scanner 128

77 For instance, in healthy individuals an association [25, 26]. Interestingly, some of these studies have also 129

78 between a face-name associative memory test and found evidence of memory-related activity in entorhi- 130
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79 amyloid deposition was found in brain regions under- nal [27] and parahippocampal [25, 28] cortex, regions 131

80 lying memory [18]. Delayed associative face-name which in AD are affected by tau-pathology even 132

81 recall has been found to be impaired in amnestic MCI earlier than the hippocampus [29]. The associative 133

82 patients and was the memory test that best predicted recognition format has also the practical advantage 134
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83 conversion from MCI to AD within two years [19]. of being easier, both subjectively and objectively, 135

84 Face-name association has obvious “face validity”, than recalling a name when shown the face alone. 136

85 because it relates to a common everyday cogni- This might avoid floor effects when studying subjects 137

86 tive complaint of elderly individuals. However, other with mild cognitive deficits. Thus, such a test can be 138
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87 associative memory tests may also be useful for administered to both normal and subjects with MCI, 139

88 early detection of AD. In particular, the CANTAB which is harder to do with free recall paradigms. In 140

89 Paired Associates Learning (CANTAB-PAL) [20] is addition, the response format may also reduce feel- 141

90 a widely employed visual-spatial paired associate ings of threat and frustration in subjects who are 142

91 learning test, which discriminated between non- concerned about their memory. 143

92 demented memory clinic patients with or without The computerized presentation of the FNART also 144

93 subsequent progression to AD dementia [21], and allowed assurance of a minimal exposure time of the 145

94 in one study was sensitive to progressive memory face-name associations in order to control depth of 146

95 decline in cognitively normal subjects with memory encoding, and enables the exploration of decision 147
 A. Polcher et al. / Associative Recognition in SCD and MCI 3

148 times during recognition, which may yield additional MCI was defined by an impaired cognitive perfor- 195

149 diagnostic information. mance (below –1.5 SD) in at least one subtest on the 196

150 The main objective of the current study was to CERAD Plus test battery (see below). This decline in 197

151 examine whether the FNART would discriminate not cognitive function was noticed either by the patient, 198

152 only between MCI and HC, but also between SCD an informant, or a clinician. 199

153 and HC. SCD was defined in line with recently proposed 200

154 We also wanted to examine whether specific com- recommendations [3], i.e., by normal cognitive per- 201

155 plaints about cognitive functions, at least in the SCD formance (defined as: all CERAD Plus subtests 202

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156 group, might be related with, and possibly reflect, within 1.5 SD; Mini-Mental-State Exam (MMSE) 203

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157 objective memory function. We assessed complaints score ≥ 28) and by self-experienced cognitive decline 204

158 about everyday cognitive functioning by the self- with worries. The latter was operationalized with the 205

159 rating version of the Everyday Cognition (ECog) following procedure: We assessed global and mem- 206

160 questionnaire. ory specific SCD, each by two consecutive questions. 207

161 Furthermore, we explore whether performance on We first asked participants “Do you feel like your 208

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162 FNART is related to performance on CANTAB-PAL, global cognitive performance has become worse?” 209

163 which requires the recall of previously learned object- (possible answers: yes/no). In case of a positive 210

164 position associations. response to this initial question we further specified 211

165 We hypothesized that the FNART and the whether global SCD was experienced as worrisome 212

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166 CANTAB-PAL would be moderately correlated, as by asking “Does this worry you?” (possible answers: 213

167 both are paired associate tasks which, however, dif- yes/no). The same procedure was done for memory 214

168 fer in item content. The number of subjects with data (“Do you feel like your memory has become worse?”). 215

169 on CANTAB-PAL performance is smaller because Self-experienced cognitive decline with worries was 216

170 this test became available to us only after the study defined by endorsement of perceived decline with 217
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171 of the FNART had started. worries in global cognition and/or memory. 218

HC individuals were included if they were above 219

the age of 50, reported age-appropriate cognitive 220

172 MATERIALS AND METHODS
functioning and negated self-experienced, worri- 221

some cognitive decline, assessed with the procedure 222

173 In this cross-sectional study, patients were
outlined above. HC who reported self-experienced
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223
174 recruited within the outpatient clinic at the Clini-
cognitive decline without worries were not excluded, 224
175 cal Research Center for Neurodegenerative Diseases
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because perceived deterioration was judged as an age- 225

176 (KBFZ) at the University Hospital Bonn. HC were
appropriate process. HC performed within the normal 226
177 acquired using a press release. This sample does
range in all CERAD Plus subtests (within 1.5 SD; 227
not overlap with previous cohorts from our research
MMSE score ≥ 28).
178
228
179 group [9, 12, 16].
While no quantified functional (Instrumental 229
The study was approved by the ethics committee
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180
Activities of Daily Living) data are available for 230
181 of the University of Bonn (Medical Faculty). Par-
our study sample, all MCI and SCD subjects 231
182 ticipants were informed about the study procedure
had preserved independence of functional activities 232
183 and gave their written informed consent before being
according to the physician’s judgment. 233
184 enrolled.
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Neuropsychological assessment 234

185 Participants
All participants underwent a neuropsychologi- 235
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186 61 patients (>50 years) who were referred to the cal examination, including the CERAD Plus test 236

187 memory clinic because of self or informant reported battery [30]. 237

188 cognitive deficits and 28 healthy individuals (mean The CERAD Plus test battery includes the 238

189 age: 67.46, SD = 8.12) were included in this study. following subtests: Verbal Fluency [31], Boston 239

190 Patients were classified as MCI (n = 29; mean age: Naming Test [32], MMSE [33], Word List Mem- 240

191 68.21, SD = 8.97) and SCD (n = 32, mean age: 67.97, ory [34, 35]), Constructional Praxis [34], Word 241

192 SD = 8.51) on the basis of performance on the Consor- List Recall, Word List Recognition [36], Recall 242

193 tium to Establish a Registry for Alzheimer’s Disease of Constructional Praxis, Phonemic Fluency, 243

194 (CERAD) Plus test battery. Trail Making Test A and B. Age-, sex-, and 244
 4 A. Polcher et al. / Associative Recognition in SCD and MCI

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Fig. 1. Design of the face-name-associative recognition test.
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245 education-adjusted German normative data are The depicted subjects varied in age to maximize 270

246 available at http://www.memoryclinic.ch. A sub- distinctiveness among the faces. Age-appropriate 271

247 sample (n = 46, see Table 2) was also assessed with popular German first names were selected from an 272

248 the Paired Associates Learning (PAL) test of the online database [41] to form face-name associations. 273
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249 Cambridge-Neuropsychological Automated Battery Figure 1 illustrates the encoding and recognition part 274

250 (CANTAB-PAL) [20], which requires the recognition of the FNART. 275
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251 of previously learned object-position associations.

252 In addition, all participants completed the Geriatric Encoding 276
253 Depression Scale (GDS, short version [37]) and 32 face-name associations were presented twice 277
254 the self-rating Everyday Cognition questionnaire in two blocks with a minimal exposure time of 4 s. 278
(ECog-39, 39 Items, [38]). The ECog-39 covers the
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255
The participants were instructed to read out the name 279
256 following domains of cognitive function in daily underneath the face and to memorize the association 280
257 life: Memory, Language, Visuospatial Abilities, for later retrieval. Participants moved to the next face- 281
258 and Planning, Organization, and Divided Atten- name presentation by pressing the button “space”. 282
259 tion. Patients had to rate their cognitive function Except the minimal exposure time, no time limit was
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283
260 in daily life compared to 10 years earlier with the set, but exposure time was measured and analyzed. 284
261 opportunity to answer (1) better or no change, (2) The face-name associations were randomized once 285
262 questionable/occasionally worse, (3) consistently a and appeared sequentially for each participant after- 286
little worse, and (4) consistently much worse. An
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263
wards. 287
264 “I don’t know” option is also given. Higher scores
265 represent worse cognitive function in daily life.
Recognition 288

All faces, presented in the associative recogni- 289

266 Stimuli and procedure tion task, were repetitions of faces encountered twice 290

in the encoding phase. Each of the 32 faces was 291

267 Pictures of 16 male and 16 female faces (20–80 shown with two names underneath: the associated 292

268 years) with neutral face expressions [39], were name and a distractor name, which had been associ- 293

269 obtained from an American face database [40]. ated with another face during encoding. Each name 294
 A. Polcher et al. / Associative Recognition in SCD and MCI 5

295 was presented twice during recognition (as target and tive memory performance we calculated one-tailed 343

296 distractor). Thus, associative recognition is based on tests. 344

297 memory recollection and not on item familiarity [42]. For the CANTAB-PAL, we included the variable 345

298 Position of the correct name versus distractor name total error adjusted in our analysis, as it was found to 346

299 was randomized across trials. be most efficient in differentiating aMCI, AD, and HC 347

300 The participants were instructed to recognize the among all PAL variables and high correlations with 348

301 names associated with each face during encoding and other PAL variables were reported [44]. The variable 349

302 to indicate the correct name via key press. No time PAL Total errors (adjusted) “reports the total num- 350

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303 limit was set, but response times were measured. ber of errors with an adjustment for each stage not 351

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304 Trials were presented in a pseudorandomized fixed attempted due to previous failure” [45]. Furthermore, 352

305 order. The randomization of trial presentation was the variable PAL Total error (6 shapes, adjusted) was 353

306 restricted: after a name’s first presentation, the same included [46]. This variable reports the number of 354

307 name was not shown in the next five trials. errors made at 6-pattern stage, with an adjustment 355

for those who not attempted this stage due to previous 356

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308 Equipment failure [45]. Higher scores represent worse memory 357

performance. 358

309 The memory test was developed in E-Studio, The correct responses in the FNART (max. 32) 359

310 Eprime 2.0 Professional [43]. Color face pictures were used to calculate a recognition score ([cor- 360

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311 were presented on a white background and names rect responses/max. correct responses] * 100). We 361

312 were presented in font Verdana size 15. Another recorded the time (ms) of encoding the face and the 362

313 E-prime application called E-Run was used to run name beyond the minimal exposure time of five sec- 363

314 the memory test. The test was presented on a laptop onds and the manual response time (RT, ms) in the 364

315 with 39 cm. The distance between the screen and the recognition part for correct and incorrect responses. 365
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316 participant were approximately 60 cm. Additionally, we calculated the difference between 366

mean RT for correct and incorrect answers. The cor- 367

317 Statistical analysis relation between the number of correct responses (%) 368

and RT difference was also determined. In addition, 369

318 Demographic and neuropsychological data were we calculated the CERAD total score [47] of the three 370

analyzed using SPSS Statistics 21. 29 MCI patients, groups as an overall measure of cognitive function, by
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319 371

320 32 SCD patients, and 28 HC were included in the summing the raw scores of the following subtests of 372
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321 analyses. In order to examine group differences the CERAD test battery: verbal fluency (with a max- 373

322 in the total sample (N = 89) and in the reduced imum of 24 points), Boston Naming Test, Word List 374

323 sample (n = 46; HC: n = 13, SCD: n = 18, MCI: Learning, Constructional Praxis, Word List Recall 375

324 n = 15), which also performed the CANTAB-PAL, we and Word List Recognition. The CERAD global score 376

325 applied Chi-Quadrat-tests for categorical and Analy- is an established measure to detect and predict MCI 377
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326 ses of Variance (ANOVAs) for continuous variables, and dementia [48]. 378

327 respectively. Following the ANOVA, we performed

328 planned comparisons (significance level ≤ 0.05).
329 We included covariates (age, level of education, RESULTS 379
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330 GDS score) in the analyses, if groups differed at least

331 tendencially regarding the covariates and if a rela- Descriptive statistics of the three groups are listed 380

332 tionship between the covariates and the dependent in Table 1. The groups did not differ significantly 381

333 variable was present. with regard to age (F(2,86) = 0.056, p = 0.946), years 382
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334 Daily functioning assessed with the ECog-39 were of education (F(2,86) = 0.181, p = 0.835) or distri- 383

335 analyzed by calculating the sum of all items com- bution of gender (χ2 (2, N = 89) = 1.632, p = 0.442). 384

336 pleted in each of the functional domains divided by However, the GDS score did differ significantly 385

337 the number of items completed in each domain. Addi- between the groups (F(2,82) = 10.705, p < 0.001), 386

338 tionally, a total score was calculated. Associations such that SCD and MCI patients had higher scores 387

339 between ECog-39 scores and memory perfor- than HC. 388

340 mance on FNART were investigated with Pearson As expected by group definition, comparisons 389

341 correlations. As we expected a negative relationship including the CERAD total score indicated a signif- 390

342 between higher ECog-39 scores and lower objec- icantly lower overall performance in the MCI group 391
 6 A. Polcher et al. / Associative Recognition in SCD and MCI

Table 1
Descriptive statistics of the study sample and group comparisons.
Whole study sample (N = 89) Group comparison
HC (n = 28) SCD (n = 32) MCI (n = 29) MCI SCD SCD
versus HC versus HC versus MCI
M SD M SD M SD p-value p-value p-value
Male/female (n) 12/16 19/13 15/14 – – – –
Age, years 67.46 8.12 67.97 8.51 68.21 8.97 1.0 1.0 1.0
Education, years 14.54 3.12 14.25 2.82 14.07 2.94 1.0 1.0 1.0

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GDS 0.68 1.44 3.26 2.44 3.35 3.22 0.000∗∗∗ 0.000∗∗∗ 1.0

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CERAD Total Score 89.57 5.72 87.06 6.18 73.79 10.61 0.000∗∗∗ 0.651 0.000∗∗∗
Contrasts
FNART
Associative Recognition 74.90 11.65 65.00 13.40 60.40 8.66 0.000∗∗∗ 0.001∗∗ 0.122
RT (Hit), ms 4898 1402 5297 1496 6448 2513 0.002∗∗ 0.411 0.956
RT (Error), ms 5598 2040 6432 2612 6396 2771 0.232 0.202 0.018∗

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RT differences, ms –700∗ 1617 –1135∗ 2138 52 1735 0.130 0.368 0.015∗
ET overall, ms 6548 981 7571 2554 7427 1724 0.085 0.041∗ 0.769
ECog-39 (adjusted for
depression)
Global Cognition 1.22 0.22 1.68 0.45 1.66 0.36 0.006∗∗ 0.004∗∗ 0.954
Everyday Memory 1.36 0.37 2.35 0.78 2.37 0.59 0.000∗∗∗ 0.000∗∗∗ 0.839

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Everyday language 1.27 0.31 1.75 0.47 1.65 0.49 0.063 0.008∗∗ 0.418
Everyday Vis spat 1.04 0.09 1.35 0.57 1.38 0.38 0.038∗ 0.065 0.730
Everyday Planning 1.11 0.26 1.38 0.60 1.36 0.38 0.557 0.543 0.997
Everyday Organization 1.21 0.37 1.37 0.55 1.38 0.44 0.867 0.654 0.770
Everyday Divided Attention 1.32 0.41 1.87 0.66 1.80 0.58 0.115 0.052 0.742
HC, healthy controls, SCD, subjective cognitive decline; MCI, mild cognitive impairment; GDS, Geriatric Depression Scale; ET, encoding
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time; RT, response time; ∗ p < 0.05; ∗∗ p < 0.01; ∗∗∗ p < 0.001.

392 (M = 73.79, SD = 10.61) compared to HC (M = 89.57,

393 SD = 5.72, p < 0.000) and SCD. However, HC and
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394 SCD (M = 87.06, SD = 6.18) did not differ signifi-

395 cantly (p = 0.651).
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396 Associative recognition (FNART)

397 FNART performance of the three groups is

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398 shown in Table 1 and Fig. 2, respectively. We

399 observed a significant effect of group on test
400 performance (F(2,86) = 11.929, p < .001). Planned
401 contrasts indicated significantly worse face-name
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402 associative memory in the MCI group (M = 60.35,

403 SD = 8.66, p < 0.001, d = 1.39) and also in the SCD
404 group (M = 64.95, SD = 13.40, p = 0.001, d = 0.78) Fig. 2. Group comparisons regarding performance on the FNART
405 compared to HC (M = 74.74, SD = 11.65). Test per- (∗∗ p < 0.01 versus HC; ∗∗∗ p < 0.001 versus HC; M ± SE).
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406 formance did not differ significantly between the MCI

407 and SCD group (p = 0.122, d = 0.40). FNART scores correlated with established mem- 415

408 Age (r = –0.266, p = 0.012) and years of education ory tests of the CERAD test battery, i.e., with word 416

409 (r = 0.256, p = 0.015) were significantly correlated list learning (r = 0.413, p < 0.001), word list recall 417

410 to performance on the FNART whereas GDS score (r = 0.446, p < 0.001), word list recognition (r = 0.293, 418

411 (r = 0.145, p = 0.105) was not. However, because p = 0.005), and visual recall (r = 0.345, p = 0.001) 419

412 groups differed with regard to GDS, we also ran the as well as with the CERAD total score (r = 0.429, 420

413 analysis including GDS as a covariate with almost p = 0.000) and with performance on CANTAB-PAL 421

414 identical results. (total errors adjusted, r = –0.547, p < 0.000). 422
 A. Polcher et al. / Associative Recognition in SCD and MCI 7

Table 2
Descriptive statistics of the study sample and group comparisons for the reduced sample with CANTAB PAL testing.
Reduced study sample (with CANTAB-PAL Group comparisons
data; n = 46)
HC (n = 13) SCD (n = 18) MCI (n = 15) MCI SCD SCD
versus HC versus HC versus HC
M SD M SD M SD p-value p-value p-value
Male/female (n) 6/7 – 11/7 8/7 – – – –
Age, years 70.69 9.169 66.4 7.891 63.67 8.886 0.110 0.544 1.0

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Education, years 14.54 2.634 15.28 2.562 14.47 2.875 1.0 1.0 1.0

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GDS 0.54 0.877 3.41 2.033 4.31 3.945 0.002∗∗ 0.012* 1.0
Contrasts
FNART (adjusted for age)
Associative Recognition 76.92 11.449 68.90 14.643 58.55 7.933 0.000∗∗∗ 0.003∗∗ 0.001∗∗
RT (Hit), ms 5207 1518 5208 1391 6026 2200 0.232 0.979 0.183
RT (Error), ms 6346 2385 5643 2043 6792 3273 0.354 0.793 0.188

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RT differences, ms –1139 1751 –1584 2633 384 1598 0.032∗ 0.752 0.007∗∗
ET, ms 1817 998 2805 2855 2535 2181 0.628 0.333 0.634
CANTAB PAL (adjusted for age)
Total errors adjusted 30.85 27.48 33.89 34.89 75.60 52.45 0.000∗∗∗ 0.249 0.000∗∗∗
6 shapes total error adjusted 7.15 5.414 10.00 11.672 21.60 18.043 0.000∗∗∗ 0.149 0.001∗∗
Stages completed 7.77 0.439 7.61 0.608 6.87 1.302 0.000∗∗∗ 0.174 0.002∗∗

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HC, healthy controls; SCD, subjective cognitive decline; MCI, mild cognitive impairment; GDS, Geriatric Depression Scale; ET, encoding
time; RT, response time; M, mean, SD, standard deviation, ∗ p < 0.05; ∗∗ p < 0.01; ∗∗∗ p < 0.001.

423 Subgroup analysis in patients showed that Response times during recognition (FNART) 451

424 performance on FNART was highly correlated

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425 with performance on CANTAB-PAL (total errors The groups differed regarding the RT of correct 452

426 adjusted, p = –0.628, p = 0.005) and the CERAD total responses (F(2,86) = 5.364, p = 0.006). MCI patients 453

427 score in the SCD group (r = 0.460, p = 0.008) but not (M = 6448 ms, SD = 2513 ms) needed more time to 454

428 in the MCI group. indicate the correct name than controls (M = 4898 ms, 455

SD = 1402 ms; p = 0.002, d = 0.75). However, RTs of 456

d

incorrect responses were similar between the groups 457

429 Encoding times during learning (FNART)
(F(2,86) = 1.023, p = 0.364). 458
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Within-group comparisons showed significantly 459

430 While analyses did not show a significant effect of
faster RTs for correct compared to incorrect responses 460
431 group on ET (F (2, 86) = 2.455, p = 0.092), planned
in SCD patients (p = 0.005) and HC (p = 0.030). How- 461
432 contrasts revealed significant differences in ET
ever, MCI patients had comparable mean RT for 462
433 between HC (M = 6548 ms, SD = 981 ms) and SCD
correct and incorrect responses (p = 0.874).
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463
434 (M = 7571 ms, SD = 2554 ms, p = 0.041, d = 0.51).
Across all groups, RT for correct and incorrect 464
435 HC and MCI (M = 7427, SD = 1724) did not differ
responses was not related to the number of cor- 465
436 significantly in ET (p = 0.085), possibly as a result of
rect responses (r = –0.177, p = 0.097 and r = –0.135, 466
437 the large RT variation in MCI.
p = 0.207). 467
Across all groups, encoding time (ET) during
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438
However, RT differences for correct and incor- 468
439 learning was significantly related to RT in the
rect responses were negatively related to FNART 469
440 subsequent associative recognition task (r = 0.460,
recognition accuracy (r = –0.308, p = 0.003), which 470
441 p < 0.001). Subgroup analyses showed that this effect
indicates that better performance on the FNART
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471
442 was only present in HC (r = 0.473, p = 0.011) and
involves greater RT difference regarding correct and 472
443 SCD r = 0.636, p < 0.001) but not in MCI (r = 0.309,
incorrect responses. 473
444 p = 0.103). ET was related to subsequent recognition
445 performance neither in the whole group (r = 0.076,
446 p = 0.481) nor any subgroup. Thus, longer viewing Everyday cognition (ECog-39) 474
447 during learning did not result in better memory per-
448 formance, and differential viewing times could not All ECog-39 functional domains were highly cor- 475
449 explain the group differences in associative memory related with depression (e.g., ECog Total score: 476
450 performance. r = 0.571, p < 0.001). The following results are 477
 8 A. Polcher et al. / Associative Recognition in SCD and MCI

CERAD learning, delayed recall and recognition, to 506

the CERAD total score, nor to the CANTAB PAL 507

total errors adjusted score. 508

Results for the reduced sample with 509

CANTAB-PAL data 510

Descriptive statistics of the three subgroups are 511

f
listed in Table 2. They did not differ significantly in 512

roo
age (F(2,43) = 2.347, p = 0.108), years of education 513

(F(2,43) = 0.461, p = 0.634) or in distribution of gen- 514

der (χi2 (2, n = 46) = 0.690, p = 0.708). However, the 515

GDS score did differ significantly between the groups 516

(F(2,40) = 7.813, p = 0.001). Despite insignificant 517

rP
group differences, we included age as a covariate to 518

account for minor group differences, as it was corre- 519

lated with cognitive performance. 520

tho
Fig. 3. Global and domain specific deterioration of cognitive Associative recognition (FNART) 521

function (ECog-39; M ± SE). ECog reported deterioration is

depicted in raw score means (scaled as: 1 = better or no change, The FNART discriminated between the groups also 522
2 = questionable/occasionally worse, 3 = consistently a little worse,
and 4 = consistently much worse, see method section for details).
in the reduced sample (F(2,42) = 19.734, p < 0.001). 523

Planned contrasts showed again worse FNART per- 524

Au
formance in MCI (p < 0.001, d = 1.8) and SCD 525

478 adjusted for GDS scores. SCD and MCI patients (p = 0.003; d = 0.58) as compared to controls. 526

479 reported significantly more difficulties than HC

480 in everyday cognition in the functional domain Associative recognition (CANTAB-PAL) 527

481 of Everyday Memory and on Global Cognition.

Additionally, significant differences were present Age was significantly correlated with test perfor-
d

482 528

483 between MCI and HC with regard to Everyday Visu- mance (Total errors: r = 0.364, p = 0.013; PAL Total 529
cte

484 alspatial Abilities and between SCD and HC with Errors adjusted: r = 0.318, p = 0.031) while depres- 530

485 regard to Everyday Language (Table 1, Fig. 3). sive symptoms were not significantly correlated with 531

486 Neither MCI nor SCD patients reported more any of the PAL variables. 532

487 deficits in executive functioning on ECog-39 (Every- The CANTAB-PAL discriminated between MCI 533

488 day Planning, Everyday Organization and Everyday and HC regarding the total number of errors adjusted 534
rre

489 Divided Attention) than HC (see Table 1), although (p < 0.001; d = 1.0), the errors made at 6 pattern stage 535

490 SCD tended to report more deficits than controls in (p < 0.001; d = 1.0) and the number of stages com- 536

491 dividing their attention (p = 0.052). pleted (p < 0.001, d = 0.92), adjusted for the effect of 537

492 Across all groups, correlations indicated a signif- age. However, differences between SCD and HC were 538
co

493 icant relationship of performance on FNART with not significant for any of the PAL variables. 539

494 ECog Total score (r = –0.250, p = 0.023), ECog Mem-

495 ory (r = –0.323, p = 0.003) and ECog Visualspatial Everyday cognition (ECog-39) 540

496 Abilites (r = –0.230, p = 0.037).

Un

497 Within the SCD group, subjective functional Adjusted for GDS scores, performance on 541

498 memory difficulties (ECog Memory subscore) were CANTAB-PAL (total errors adjusted) was not related 542

499 significantly related to recognition accuracy on to any of the ECog scores for all in the subsample 543

500 FNART (r = –0.365, p = 0.024) but neither to learn- (n = 46). Likewise, within the SCD group the correla- 544

501 ing, delayed recall and recognition on CERAD tion between ECog Memory and CANTAB-PAL total 545

502 test battery nor to the CERAD total score and to errors adjusted (r = 0.380) did not reach statistical sig- 546

503 total errors adjusted on CANTAB PAL. Within the nificance (p = 0.073), possibly due to a small sample 547

504 MCI sample, subjective functional memory deficits size (n = 14). The same comparison within the MCI 548

505 were neither related to performance on FNART, to group revealed no significant relationship between 549
 A. Polcher et al. / Associative Recognition in SCD and MCI 9

550 CANTAB-PAL total errors adjusted and any of the apparent than real. However, if substantiated with 600

551 ECog scores. larger samples, such a dissociation could result from 601

face-name association being more reliant on extrahip- 602

552 DISCUSSION pocampal brain regions [25] where tau pathology 603

occurs early in the course of AD. 604

553 The aim of the present study was to investigate Although the association of both tests were sub- 605

554 whether associative recognition memory is a sensitive stantial (r = –0.547) as expected given both are 606

555 measure for detection of subtle memory impairment. associative learning tests, the above mentioned 607

f
556 We found that associative recognition on the demand- specifics as, e.g., abstract visual-spatial versus 608

roo
557 ing FNART is not only impaired in MCI but also in ecologically valid face-verbal associations and dif- 609

558 individuals with SCD who performed normal on tests ferential involvement of executive functions may 610

559 of an established neuropsychological battery. account for the fact that both still share less than 30% 611

560 Our finding of a slowing in memory RT in MCI variance. 612

561 cases is consistent with other findings previously Within the MCI sample we observed a floor effect 613

rP
562 reported for AD cases [49, 50] and could be indica- in the FNART performance indicated by near chance 614

563 tive for a general cognitive slowing associated with level (50%). This effect is due to the relatively high 615

564 the disease, memory search and the absence of con- task difficulty of the FNART. Therefore, the use 616

565 fidence. of this test could be limited regarding follow-up 617

tho
566 While RT for correct choices was faster in HC (in examinations within MCI and AD samples and the 618

567 line with previous findings [51]) and SCD, RT for discrimination between MCI and more impaired AD 619

568 correct and incorrect decisions did not differ in MCI patients. On the other hand, it is advantageous for the 620

569 cases. The difference in RT was negatively related to detection of subtle cognitive impairment in individ- 621

570 recognition accuracy on FNART. This suggests that uals with SCD and preclinical AD, i.e., our primary 622
Au
571 the ease of successful retrieval is reflected in both, target population. 623

572 better and faster recognition. In subjects with MCI, There is accumulating evidence showing that 624

573 accuracy (58%) was only slightly better than chance memory clinic patients with self-experienced cog- 625

574 (50%), so that their decisions were largely based on nitive decline and normal test performance have 626

575 guessing rather than on associative retrieval. Whether increased risk for abnormal levels of AD biomarkers 627

of amyloidosis and tau-mediated neurodegeneration

d

576 or not the RT differences in forced-choice memory 628

577 paradigms will yield additional diagnostic informa- and dysfunction [9, 11, 13]. Furthermore, biomarker 629
cte

578 tion beyond accuracy is an interesting issue in need evidence is relevant for clinical decision making 630

579 of further research. and prediction of future cognitive decline and is of 631

580 In a reduced sample we observed similar results particular importance for the characterization of pre- 632

581 regarding FNART performance across the three clinical AD [3]. In this study, information on CSF 633

582 groups. In addition, performance on the short biomarker status was available only in a minor num- 634
rre

583 visual memory test CANTAB-PAL, which requires ber of patients. Biomarker positivity versus negativity 635

584 the recognition of previously learned association might account for the observed variability in test per- 636

585 between an abstract (nonverbal) object and a spa- formance especially in SCD cases, beside the extent 637

586 tial location, was impaired in MCI—as previously of cognitive reserve and coexisting pathologies or 638
co

587 shown [52, 53]—but not in SCD. Impairment in diseases. Further studies incorporating data on AD 639

588 associative memory performance on CANTAB-PAL biomarkers will clarify whether the FNART can dis- 640

589 in aMCI cases was shown to be determined by a criminate between SCD/MCI cases due to AD and 641

590 decrease of short-term memory capacity, difficul- SCD/MCI due to other causes. 642
Un

591 ties with memory consolidation and less effective Self-reported cognitive function in daily life is 643

592 executive functioning as, e.g., reduced response associated cross-sectionally [54, 55] and longitu- 644

593 monitoring [53]. Thus, preserved executive func- dinally [56] with episodic memory and executive 645

594 tioning in SCD cases may account for the normal functioning. In our study, we assessed function in 646

595 recognition performance on CANTAB-PAL. Because daily life with the self-rating instrument “Everyday 647

596 of the small sample sizes and the limited power to dis- Cognition” (ECog-39). In the current study, patients 648

597 criminate SCD from HC with the CANTAB-PAL, the with MCI and SCD complained particularly about 649

598 dissociation between the two paired associate tasks difficulties in everyday memory. All patients were 650

599 regarding their sensitivity to SCD might be more recruited in a memory clinic, and memory complaints 651
 10 A. Polcher et al. / Associative Recognition in SCD and MCI

652 are the most prominent complaint in these settings, (Memory Capacity Test from H. Buschke). Further- 704

653 and part of the definition of MCI and most SCD more, composites of traditional, challenging tests 705

654 criteria. Thus it is not a surprise to us that patients (e.g., Preclinical Alzheimer Cognitive Composite 706

655 differ from controls on the memory subscale, but that [65]) with proposed sensitivity to early AD related 707

656 this is a rather specific complaint not evident for the changes have been developed. At present, there are 708

657 other functions assessed with the ECog. Interestingly, yet not enough comparative data in the ability of 709

658 self-reported memory difficulties were significantly these tests to identify biomarker-defined AD in the 710

659 related to FNART performance in the SCD group, but preclinical or prodromal stages of the disease. 711

f
660 not in MCI. In the subgroup analysis, self-reported In summary, findings of this study suggest that 712

roo
661 memory difficulties tended toward significance with associative recognition is a sensitive neuropsy- 713

662 CANTAB-PAL performance for SCD but not MCI. chological measure for detecting subtle cognitive 714

663 This suggests that some subjects with SCD correctly impairment in memory-clinic subjects with SCD, a 715

664 sense and report minor memory deficits, which can group known to be at increased risk for having pre- 716

665 be unmasked only with challenging tests like the clinical AD. Thus, the FNART, together with other 717

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666 FNART or the CANTAB-PAL. No such relationships recently developed tests [17, 16], could be a useful 718

667 were found in the MCI sample. This might be due to supplement to established test batteries for obser- 719

668 a reduced awareness of cognitive deficits and their vational and intervention studies in memory clinic 720

669 impact on daily activities/everyday function in some patients. 721

tho
670 MCI cases, consistent with previous studies [57–59]. Further longitudinal and biomarker studies should 722

671 Underestimation of functional deficits in MCI has examine the predictive validity of the FNART and 723

672 been associated with a CSF biomarker profile indica- aim to identify factors that influence the variability in 724

673 tive of AD and progression to AD [57, 58]. associative memory accuracy in MCI and especially 725

674 As also reported in previous studies [57], func- in SCD cases. 726
Au
675 tional deficits in our MCI and SCD cases were linked
676 to depressive symptoms.
677 In sum, our results provide further evidence that ACKNOWLEDGMENTS 727

678 associative memory assessment is not only sensitive

679 for age-related cognitive decline in episodic mem- We would like to cordially thank M.Sc. Lisa 728

ory function in healthy elderly (Associative Deficit Miebach, B.Sc. Luca Kleineidam, Sandra Röske,
d

680 729

681 Hypothesis [60]) but also for detecting subtle cogni- PhD, Dipl.-Psych. Catherine Widmann, Annika Spot- 730

tke, MD and Klaus Fließbach, PhD, Department of

cte

682 tive decline that might be attributed to AD pathology, 731

683 Thus, associative memory assessment seems to Psychiatry, University of Bonn and German Center 732

684 be suitable for the investigation of subtle cognitive for Neurodegenerative Diseases, Bonn, Germany for 733

685 deficits in preclinical AD. Most assessment batteries further support of this study and manuscript. 734

686 in this field rely on non-associative item memory, the This work was funded by the DZNE, German Cen- 735
rre

687 inclusion of a short associative memory test might be ter for Neurdegenerative Diseases, Bonn, Germany. 736

688 a useful complement. Several studies found associa- Authors’ disclosures available online (http://j-alz. 737

689 tive memory to be more impaired than item-memory com/manuscript-disclosures/160637r2). 738

690 in healthy elderly [61] and MCI [62] and our findings
co

691 would be consistent with an early sensitivity of asso-

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