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

DOI 10.3233/JAD-171180
IOS Press

1 From Subjective Cognitive Decline to


2 Alzheimer’s Disease: The Predictive Role
of Neuropsychological Assessment,

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4 Personality Traits, and Cognitive Reserve.
5 A 7-Year Follow-Up Study

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6 Valentina Bessia,∗ , Salvatore Mazzeoa , Sonia Padiglionia , Carolina Piccinic , Benedetta Nacmiasa ,
7 Sandro Sorbia,b and Laura Braccoa

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a Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence,
9 Italy
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b IRCCS Don Carlo Gnocchi, Florence, Italy

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c Neurology Unit, Local Health Unit 10, Florence, Italy Au
Accepted 5 April 2018

12 Abstract. The aim of this study was to evaluate the accuracy of neuropsychological assessment in predicting conver-
13 sion from subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and the
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14 effect of personality traits and cognitive reserve in progression from SCD to MCI. As part of a longitudinal, clinical-
15 neuropsychological-genetic survey on SCD and MCI, 284 patients referred to our hospital between 1990 and 2017 were
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16 included. All patients underwent clinical-extensive neuropsychological evaluation and Apolipoprotein E genotyping; per-
17 sonality traits were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up. Subjects with a
18 follow-up shorter than two years were excluded. A total of 212 subjects were, after exclusions, considered: 26 out of 109 SCD
19 subjects progressed to MCI (SCD-p), 15 converted to AD (SCD-c), and 68 remained stable (SCD-s). Of 103 MCI subjects,
20 39 converted to AD (MCI-c) and 64 remained stable (MCI-s). At baseline, SCD-c performed significantly worse than SCD-s
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21 in tests assessing long-term verbal memory. MCI-c showed worse performance on neuropsychological tests for short- and
22 long-term verbal memory and for ecological evaluation of memory (RBMT). These tests provided good accuracy in distin-
23 guishing MCI-c and MCI-s. Emotional stability was significantly lower in SCD-s than in SCD-p while higher intellectual
24 activities were associated with a lower risk of conversion to MCI. Our results suggest that memory neuropsychological tests
may represent a reliable tool to estimate the risk of progression to AD. Personality and lifestyle factors could provide useful
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26 information to identify SCD subjects who may develop an objective cognitive impairment.

27 Keywords: Alzheimer’s disease, APOE, cognitive reserve, dementia, mild cognitive impairment, neuropsychology, person-
ality traits, prediction, subjective cognitive decline
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28

INTRODUCTION 29

Alzheimer’s disease (AD) has a slow and pro- 30


∗ Correspondence to: Valentina Bessi, Department of Neuro- gressive trend, with a presymptomatic course which 31
science, Psychology, Drug Research and Child Health, University
of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo
can last from several years to decades [1, 2]. Iden- 32

Brambilla, 3, 50134, Florence, Italy. Tel.: +39 05 7948660; Fax: tification of subjects at an early stage is crucial for 33

+39 05 7947484; E-mail: valentina.bessi@tin.it. therapeutic intervention and possible prevention of 34

ISSN 1387-2877/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved
2 V. Bessi et al. / Predicting Conversion from SCD and MCI to AD

35 cognitive decline. Current research is focused on iden- to AD. On the other hand, to our knowledge, only few 87

36 tifying characteristics of the early stages of AD and longitudinal studies investigated prognostic value of 88

37 several concepts have been developed to that end [3, 4]. neuropsychological assessment at baseline in sub- 89

38 The concept of mild cognitive impairment (MCI) jects with SCD in developing MCI and AD [18–21], 90

39 evolved over the past two decades to define subjects often with conflicting results. 91

40 at the transitional stage between normal aging and A number of papers have tackled the question of 92

41 dementia. Evidence from cross-sectional and lon- whether premorbid personality traits are linked to the 93

42 gitudinal studies has shown that MCI is associated risk of developing MCI [22, 23] and AD [24–27]. 94

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43 with an increased risk of positive AD biomark- Most studies agree that high conscientiousness and 95

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44 ers and with an annual conversion rate of 5–17% low neuroticism are associated with a reduced risk of 96

45 to AD. Different conditions, either neurodegenera- incident AD [27, 28]. 97

46 tive or non-degenerative (cerebrovascular, infective, Finally, several studies have reported that educa- 98

47 metabolic or pharmacological), may underlie MCI. tion [29], intellectually engaging occupations [30], 99

48 Reversion to normal cognition is also possible in MCI and a cognitive [32], physical [33], and socially inte- 100

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49 subjects [5]. grated lifestyle may protect against dementia [34]. 101

50 Subjective cognitive decline (SCD) was defined These findings have been interpreted by means of the 102

51 as a self-experienced persistent decline in cognitive Cognitive Reserve hypothesis [35, 36]. 103

52 capacity in comparison with the subject’s previously The aim of the present study is to evaluate the 104

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53 normal status, during which the subject has normal prognostic accuracy of neuropsychological tests in 105

54 age-, gender-, and education-adjusted performance predicting conversion from SCD and MCI to AD and 106

55 on standardized cognitive tests [6]. the role of personality traits and cognitive reserve 107

56 Nevertheless, studies of patients with SCD in popu- in increasing or reducing the risk of progression to 108

57 lations aged over 75 have described neuroradiological objective cognitive impairment in subjects experienc- 109
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58 features similar to those seen in AD patients, such as ing SCD. 110

59 volume loss in hippocampal/parahippocampal areas


60 [7] and evidence of amyloid deposition using PET- MATERIALS AND METHODS 111

61 imaging [8]. Longitudinal biological studies showed


62 that SCD at baseline is linked with subsequent change Participants and clinical assessment 112

in hippocampal volume [9] and a recent meta-analysis


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64 suggested that older people with SCD are twice as As part of a longitudinal, clinical-neuro- 113
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65 likely to develop dementia as individuals without psychological-genetic survey on SCD and MCI, we 114

66 [10, 11]. included 284 consecutive spontaneous subjects who 115

67 SCD could be related to numerous conditions such self-referred to the Centre for Alzheimer’s Disease 116

68 as normal aging, psychiatric, neurological or medical and Adult Cognitive Disorders of Careggi Hospital 117

69 disorders, substance use or medication [12]. The great in Florence between March 1990 and March 2017. 118
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70 majority of SCD subjects are ‘worried well’ and do All participants underwent a comprehensive fam- 119

71 not deteriorate more rapidly than usual [9]; disappear- ily and clinical history, general and neurological 120

72 ance of the subjective sensation of cognitive decline examination, extensive neuropsychological investi- 121

73 is also common [14]. gation, and estimation of premorbid intelligence as 122


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74 As a result, individuals with SCD and MCI con- well as assessment of depression. A positive family 123

75 stitute a heterogeneous group. Therefore, estimating history was defined as one or more first-degree rela- 124

76 the probability that SCD and MCI are related or not tives with documented cognitive decline. Cognitive 125

77 to AD is a fundamental aim for people experiencing complaints were explored during the neurological 126
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78 objective or subjective cognitive decline as well as interview at baseline by using a survey based on the 127

79 for targeting dementia prevention [12]. Memory Assessment Clinics-Questionnaire [37]. We 128

80 The accuracy of cognitive tests in predicting defined the presence of cognitive complaints if partic- 129

81 progression from MCI to AD has been widely ipants perceived decline in cognitive capacity than in 130

82 investigated. Several studies showed that low scores the past or if they reported difficulties in carrying out 131

83 in neuropsychological tests evaluating verbal and at least four of the following activities: 1) remember- 132

84 visuospatial episodic memory, abstract reasoning, ing the name of a person just introduced to them; 133

85 learning, language and executive functions [16–20] 2) recalling telephone numbers or zip codes used 134

86 could support the hypothesis that MCI would be due on a daily or weekly basis; 3) recalling where they 135
V. Bessi et al. / Predicting Conversion from SCD and MCI to AD 3

136 put objects (such as keys) in their home or office; 4) All patients underwent clinical and neuropsycho- 188

137 remembering specific facts from a newspaper or mag- logical follow-up every six or 12 months. Seventeen 189

138 azine article just read; 5) remembering the item(s) patients (15 SCD and 2 MCI) did not refer to our 190

139 they intend to buy when they arrive at the grocery Memory Centre for follow-up visits for more than 191

140 store or pharmacy. Out of the 284 participants, 191 two years. Therefore, to obtain relevant information 192

141 underwent APOE genotype analysis. In a subgroup on their cognitive and functional status, we conducted 193

142 of 60 subjects, we evaluated personality traits and phone interviews both with them and a relative. 194

143 leisure activities. Specifically, we asked if they still complained of 195

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144 For this study, inclusion criteria were: 1) com- cognitive decline, if they showed a clear worsening 196

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145 plaining of cognitive decline with a duration of ≥6 of cognitive functions and/or a reduction in Activi- 197

146 months; 2) normal functioning on the Activities of ties of Daily Living and the Instrumental Activities 198

147 Daily Living and the Instrumental Activities of Daily of Daily Living scale scores or whether they were 199

148 Living scales [38]; 3) unsatisfied criteria for demen- followed-up by other clinicians specialized in cog- 200

149 tia at baseline [39, 40]; 4) attainment of the clinical nitive disorders, if they received a diagnosis either 201

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150 endpoint, i.e., conversion to MCI according to the of MCI or AD or other neurodegenerative disor- 202

151 National Institute on Aging-Alzheimer’s Association ders, if they started therapy with acetyl-cholinesterase 203

152 (NIA-AA) criteria [3], and conversion to AD accord- inhibitors or memantine. 204

153 ing to the NIA-AA criteria [40] during follow up, On the basis of progression from SCD to 205

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154 regardless of follow-up duration; 5) a follow-up time MCI and AD during the follow-up, SCD sub- 206

155 of more than 2 years from the baseline visit for those jects were classified respectively into SCD-stable 207

156 patients who did not develop MCI or AD. Exclu- (SCD-s), SCD-progressed (SCD-p), and SCD- 208

157 sion criteria were: 1) history of head injury, current converters (SCD-c). In the same way, MCI subjects 209

158 neurological and/or systemic disease, symptoms of were classified as MCI-stable (MCI-s) and MCI- 210
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159 psychosis, major depression, alcoholism or other sub- converters (MCI-c). 211

160 stance abuse; 2) the complete data loss of patients’


161 follow-up; 3) progression to dementia other than AD. Neuropsychological assessment 212

162 Furthermore, as AD before the age of 65 is rare


163 and is considered to have specific diagnostic features All subjects were evaluated by means of an exten- 213

compared to dementia in the elderly [41], we also sive neuropsychological battery standardized on a
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164 214

165 excluded subjects who were younger than 65 years at group of 146 normal subjects and described in fur- 215
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166 the end of the follow-up. ther detail elsewhere [44]. The battery consisted of 216

167 From the initial sample, we excluded 41 subjects global measurements [Mini-Mental State Examina- 217

168 who did not convert to MCI or AD with a follow-up tion (MMSE), Information-Memory-Concentration 218

169 shorter than two years. We excluded one subject who Test], tasks exploring verbal and spatial short- 219

170 developed a brain tumor, seven subjects who were term memory (Digit Span; Corsi Tapping Test) 220
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171 diagnosed with other forms of dementia (six vascular and verbal long-term memory [Five Words and 221

172 dementia, according to NINDS-AIREN criteria [42] Paired Words Acquisition (FWA, PWA); Recall 222

173 and one frontotemporal dementia, according to Neary after 10 min – FWR10, PWR10; Recall after 24-h 223

174 criteria [43]); and 23 subjects were excluded as they – FWR24, PWR24; Babcock Short Story Imme- 224
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175 were younger than 65 years at the end of the follow- diate and Delayed Recall (BS, BSR)], language 225

176 up. Therefore, in the end 212 subjects were included. (Token Test; Category Fluency Task), visuo-motor 226

177 We divided this sample into two groups: 109 subjects functions (Copying Drawings). Based on a previ- 227

178 classified as SCD, according to the terminology pro- ous discriminant analysis, five tests were selected 228
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179 posed by the Subjective Cognitive Decline Initiative from the battery (FWA, PWA, FWR10, PWR24, 229

180 (SCD-I) Working Group [6] (i.e., presence of a self- Information-Memory-Concentration Test) to obtain 230

181 experienced persistent decline in cognitive capacities two Composite Memory Scores (CMS1 and CMS2), 231

182 with normal performance on standardized cogni- with positive scores indicating worse performance 232

183 tive tests); 103 subjects classified as MCI according [44]. Visuospatial abilities were also evaluated by 233

184 to (NIA-AA) criteria for the diagnosis of MCI [3] Rey-Osterrieth Complex Figure copy and visuospa- 234

185 (i.e., evidence of lower performance in one or more tial long-term memory was assessed by means of 235

186 cognitive domains with preserved independence of recall of Rey-Osterrieth Complex Figure test [45]; 236

187 function in daily life). attention/executive function was explored by means 237
4 V. Bessi et al. / Predicting Conversion from SCD and MCI to AD

238 of Dual Task [46], Phonemic Fluency Test [47], Statistical analysis 286

239 and Trail Making Test [48]. Everyday memory was


240 assessed by means of Rivermead Behavioral Memory Patient groups were characterized using means 287

241 Test (RBMT) [49]. All raw test scores were adjusted and standard deviations (SD). Scores at cognitive 288

242 for age, education and gender according to the cor- tests were reported as z-scores (z-scores were cal- 289

243 rection factor reported in validation studies for the culated as the raw score of the patient, minus the 290

244 Italian population [44–49]. In order to estimate pre- mean score of Italian general population, divided 291

245 morbid intelligence, all subjects were given the TIB by the SD of Italian general population). We tested 292

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246 (“Test di Intelligenza Breve”) [50], an Italian version for the normality distribution of the data using the 293

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247 of the National Adult Reading Test [51]. The presence Kolmogorov-Smirnov test. Depending on the distri- 294

248 and severity of depressive symptoms was evaluated bution of our data, we used t-test or non-parametric 295

249 by means of the 22-item Hamilton Depression Rating Mann-Whitney U Tests for between groups’ com- 296

250 Scale (HRSD) [52]. parisons and Pearson’s correlation coefficient or 297

non-parametric Spearman’s ρ (rho) to evaluate corre- 298

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251 Personality traits and leisure activities lations between groups’ numeric measures. We used 299

chi-square test to compare categorical data and cal- 300

252 We used the Big Five Factors Questionnaire [53] culated the effect size by Cohen’s d for numeric 301

253 to assess personality traits of the subjects. At base- measures and Cramer’s V for categorical data. We 302

line, participants had to fill out a questionnaire that used ROC curve analysis to evaluate diagnostic accu-

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254 303

255 measures the five factors of: 1) emotional stability, 2) racy, i.e., sensitivity, specificity, positive predictive 304

256 energy, 3) conscientiousness, 4) agreeableness, and value (PPV), negative predictive value (NPV), and 305

257 5) openness to culture and experience. The inven- AUC (Area Under the Curve) for neuropsychological 306

258 tory follows a widely accepted five-traits personality tests. We constructed Cox regression models to ascer- 307
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259 model [53, 54]. For the 24 items of each factor, sub- tain the effect of the variables in predicting conversion 308

260 jects rated their level of agreement on a five-point to MCI or AD. All statistical analyses were performed 309

261 scale ranging from strongly agree to strongly dis- with SPSS software v.13 (SPSS Inc., Chicago, USA). 310

262 agree. Item scores were computed for each factor The significance level was set at p < 0.05. 311

263 to yield a summary measure of the trait with higher


values representing a greater degree of the explored
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264 RESULTS 312

265 dimension.
At baseline, subjects were interviewed regarding
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266 Demographic and clinical features 313

267 participation, when they were 30–40 years old, in nine


268 Intellectual Activities, seven Social Activities and At follow up, 26 out of 109 SCD subjects (24%) 314

269 seven Physical Activities (modified from Yarnold et had converted to MCI (SCD-p) and 15 (14%) had con- 315

270 al. [55]). The frequency of participation was reported verted to AD (SCD-c). Mean conversion time from 316
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271 for each activity on a Likert scale ranging from 0 SCD to MCI was 6.53 (± 3.11) years and from SCD 317

272 to 5, where 0 refers to never, 1 to occasionally, 2 to AD was 9.14 (± 4.22) years. A total of 68 sub- 318

273 to monthly, 3 to once a week, 4 to several days per jects (62%) remained stable (SCD-s) and their mean 319

274 week and 5 to daily. We summed the scores for each follow-up time was 7.15 (± 3.88) years (range: 2.00 320
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275 activity to generate total scores for intellectual, social, – 18.48 years, IQR: 5.15 years). 321

276 physical and other activities ranging from 0 to 30. Of 103 MCI subjects, 39 (38%) developed AD 322

(MCI-c) and 62 (60%) remained stable. Two MCI 323

277 Apolipoprotein E ␧4 genotyping subjects (2%) regressed to SCD and we included 324
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them in the MCI-s group as we considered them non- 325

278 DNA was extracted from peripheral blood samples converters. Mean follow up time of MCI-s was 7.51 326

279 from all subjects by use of the phenol-chloroform (± 4.78) years (range: 2.00 – 27.20 years, IQR: 5.21 327

280 procedure, and the APOE gene was amplified in the years). 328

281 polymorphic region [56]. The frequencies of the ␧2, Annual conversion rate (ACR), cumulative conver- 329

282 ␧3, and ␧4 alleles were estimated by gene counting. sion proportion (CCP), and mean conversion time for 330

283 The APOE genotype was coded as APOE ␧4- (no MCI and AD are summarized in Table 1. 331

284 APOE ␧4 alleles) and APOE ␧4+ (presence of one or Of the 17 out patients who were included after 332

285 two APOE ␧4 alleles). a telephone call, three out of 16 SCD subjects 333
V. Bessi et al. / Predicting Conversion from SCD and MCI to AD 5
S.E. (3)

Table 1
Values quoted in the table are mean (± SD). Age at baseline, age at onset, disease duration, follow up and schooling are expressed in years. p (1) indicates level of significance for comparison
between SCD-s and SCD-p; p (2) indicates level of significance for the comparisons between SCD-s and SCD-c; p (3) indicates level of significance for the comparisons between MCI-s and MCI-c¸
(significant differences at p < 0.05, in bold characters, underlined). S.E. (1) indicates size effect for the comparisons between SCD-s and SCD-p; S.E. (2) indicates size effect for the comparisons
between SCD-s and SCD-c; S.E. (3) indicates size effect for the comparisons between MCI-s and MCI-c. *In SCD-p, SCD-c, and MCI-c groups follow up indicates conversion time to MCI and
0.77
0.85

1.12

0.52
0.03

0.31
0.10
0.41

0.16
0.29
0.02

Annual conversion rate (ACR), cumulative conversion proportion


(CCP), and mean conversion time (MCT) from SCD to MCI, from
SCD to AD, and from MCI to AD. MCT is expressed as years ± SD
<0.001
<0.001

<0.001

<0.001
0.615
0.870

0.092

0.083

0.556
0.241
0.737
p (3)

ACR CCP MCT (± SD)


SCD to MCI 3.65% 23.85% 6.53 (± 3.11)
SCD to AD 1.51% 13.76% 9.14 (± 4.32)
107.15 (± 10.751)

MCI to AD 11.65% 37.86% 3.25 (± 2.47)


71.97 (± 5.12)
68.59 (± 5.95)

3.25 (± 2.47)*

25.82 (± 2.21)

26.42 (± 3.97)
3.38 (± 2.82)
9.05 (± 4.57)
MCI-c (39)

61.90%
51.28%

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MCI

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334 developed AD (conversion time: 11.87 ± 4.83 years)


335 while 13 SCD subjects remained stable (follow-up
to AD time. MMSE, Mini-Mental State Examination; APOE, Apolipoprotein; HRSD, Hamilton Depression Rating Scale; TIB, Test di Intelligenza Breve.

336 time: 10.10 ± 3.51). Of the two MCI subjects, both


remained stable, with a follow-up time of 27.20 years
103.73 (± 12.62)

337
67.21 (± 7.025)
62.89 (± 7.41)

26.72 (± 2.15)

27.10 (± 4.62)
7.51 (± 4.78)
4.32 (± 3.24)
8.58 (± 4.46)
MCI-s (64)

338 and 10.2 years.


12.12%
54.68%

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41/22

339 In the SCD group, no significant differences were


340 found between SCD-s and SCD-p and between SCD-
341 s and SCD-c in sex, familiarity, disease duration,
342 schooling, MMSE, HRSD, and TIB. There was no
S.E. (2)

statistically significant difference in genotype dis-


tho 0.40
0.86

0.49
0.07
0.48

0.04
0.01
0.49
0.28
0.09
0.14
343
344 tribution of APOE ␧4 among the three subgroups
345 of SCD, but a trend toward significance was found
0.161
0.281
0.764
0.778
0.106
0.731
0.795
0.069
0.056
0.932
0.409
between SCD-s and SCD-c (p = 0.056).
p (2)

346
Demographic and cognitive data

347 In the MCI group, MCI-c were older than MCI-s


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348 at onset of symptoms and at baseline visit. Genotype
S.E. (1)

APOE ␧4 was more frequent in MCI-c subjects than


0.08
0.60
0.44
0.01
0.18
0.08
0.38
0.12
0.12
0.07
0.27
349
Table 2

350 MCI-s subjects (Table 2).


351 No significant differences were found between
0.960
0.813
0.440
0.937
0.892
0.640
0.117
0.601
0.319
0.909
0.281
p (1)
352 APOE ␧4 + and APOE ␧4- subjects with regards to
SCD
sex, familiarity, disease duration, age at onset, age at
353
baseline, schooling, MMSE, HRSD, and TIB. There d

110.58 (± 6.64)
354

66.91 (± 5.75)
62.53 (± 7.07)

9.14 (± 4.22)*

11.20 (± 5.39)
27.23 (± 2.56)

26.33 (± 3.69)
4.40 (± 4.08)
SCD-c (15)
were no statistically significant associations between
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46.46%

54.54%
355

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356 APOE genotype and familiarity and between APOE
357 genotype and sex. No subjects had depression accord-
358 ing to HRSD scores.
359 There were no significant correlations between

109.43 (± 8.77)
63.80 (± 8.85)
60.56 (± 7.41)

6.53 (± 3.11)*

28.07 (± 2.04)

26.38 (± 3.91)
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3.98 (± 3.24)
9.54 (± 4.17)
neuropsychological tests, personality traits and

SCD-p (26)
360

53.85%

33.33%
leisure activities. No differences were found

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361
362 in neuropsychological tests, personality traits
363 and leisure activities between APOE ␧4 + and
APOE ␧4–.

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364

111.48 (± 6.24)
64.45 (± 6.63)
55.65 (± 8.91)

11.25 (± 4.77)
28.31 (± 1.83)

26.67 (± 4.19)
7.15 (± 3.88)
4.26 (± 3.84)
SCD-s (68)

21.56 %
52.94%
44/24
365 Neuropsychological assessment

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366 In the SCD group, no significant differences were
367 found at baseline for any neuropsychological tests
between SCD-s and SCD-p (Table 3). SCD-c per-

Disease duration (± SD)


Familiarity (percentage)

APOE ␧4+ (percentage)


368

Age at baseline (± SD)


formed significantly worse than SCD-s in FWR24

Age at onset (± SD)


Sex (females/males)
369

Schooling (± SD)
Follow up (± SD)
370 test. CMS1 and CMS2 were significantly higher in

MMSE (± SD)
Demographics

HRSD (± SD)
371 SCD-c than SCD-s. No significant differences were

TIB (± SD)
372 found at baseline for any other neuropsychological
373 tests between SCD-s and SCD-c (Table 3). Con-
374 sidering those neuropsychological tests that were
6 V. Bessi et al. / Predicting Conversion from SCD and MCI to AD

Table 3
Z-score mean values for each neuropsychological test in SCD and MCI
SCD MCI
Tests SCD-s (68) SCD-p (26) SCD-c (15) p (1) p (2) MCI-s (64) MCI-c (39) p (3)
CMS1 –1.05 (± 0.21) –1.02 (± 0.20) –0.90 (± 0.22) 0.446 0.020 –0.89 (± 0.23) –0.69 (± 0.35) 0.003
CMS2 –0.56 (± 0.46) –0.56 (± 0.46) –0.27 (± 0.40) 0.946 0.044 –0.26 (± 0.48) 0.12 (± 0.72) 0.006
FWA 0.35 (± 0.96) 0.14 (± 1.05) 0.21 (± 0.75) 0.384 0.395 –0.08 (± 1.07) –0.86 (± 1.46) 0.008
FW10 0.48 (± 1.05) 0.59 (± 0.75) 0.42 (± 0.79) 0.913 0.520 0.33 (± 1.03) –1.06 (± 1.86) <0.001
FW24 –0.04 (± 0.51) –0.08 (± 0.50) –0.40 (± 0.53) 0.662 0.016 –0.32 (± 0.56) –0.74 (± 0.83) 0.009

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PWA 0.55 (± 1.08) 0.54 (± 1.07) 0.33 (± 0.81) 0.959 0.316 –0.17 (± 1.14) –0.74 (± 1.33) 0.063

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PW10 0.51 (± 0.85) 0.64 (± 0.65) 0.86 (± 0.26) 0.897 0.293 0.02 (± 1.21) –0.77 (± 1.82) 0.007
PW24 0.15 (± 1.02) 0.15 (± 0.85) 0.14 (± 0.76) 0.668 0.649 –0.38 (± 0.98) –1.02 (± 1.58) 0.042
BS 0.12 (± 0.74) –0.01 (± 0.69) 0.18 (± 0.83) 0.425 0.813 –0.63 (± 0.81) –0.97 (± 0.68) 0.046
BSR 0.56 (± 0.96) 0.46 (± 0.72) 0.64 (± 0.93) 0.441 0.934 –0.34 (± 1.03) –1.14 (± 0.76) <0.001
DS –0.71 (± 1.23) –1.02 (± 1.22) –0.98 (± 1.30) 0.287 0.451 –1.39 (± 0.97) –1.05 (± 1.46) 0.309
RBMT 0.22 (± 0.71) 0.11 (± 0.77) –0.09 (± 0.83) 0.626 0.237 –0.44 (± 1.12) –1.87 (± 1.61) <0.001

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TMTa –0.48 (± 0.80) –0.74 (± 0.58) –0.39 (± 0.49) 0.258 0.373 0.13 (± 1.21) –0.08 (± 0.88) 0.509
TMTb 0.76 (± 0.49) 0.81 (± 0.47) 0.59 (± 0.41) 0.682 0.304 0.28 (± 0.80) –0.06 (± 0.93) 0.122
TMTb-a 0.77 (± 0.48) 0.74 (± 0.53) 0.57 (± 0.42) 0.714 0.108 0.33 (± 0.85) –1.26 (± 1.03) 0.075
DT –0.18 (± 1.43) –0.08 (± 1.42) 0.55 (± 1.32) 0.794 0.104 1.09 (± 1.09) 1.20 (± 0.20) 0.426
TT 0.42 (± 0.49) 0.50 (± 1.80) 0.29 (± 0.61) 0.323 0.489 –0.19 (± 0.74) –0.23 (± 0.71) 0.670
PFT 0.23 (± 0.80) 0.34 (± 0.63) –0.11 (± 0.99) 0.565 0.207 –0.30 (± 0.73) –0.29 (± 0.76) 0.927

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CFT 0.83 (± 0.40) 0.84 (± 0.29) 0.94 (± 0.00) 0.734 0.236 0.59 (± 0.69) 0.52 (± 0.75) 0.602
CD 1.58 (± 0.53) 1.50 (± 0.47) 1.35 (± 0.62) 0.217 0.111 1.39 (± 0.70) 1.53 (± 0.56) 0.372
CT –1.28 (± 1.34) –1.11 (± 1.46) –0.88 (± 1.09) 0.631 0.155 –1.28 (± 0.93) –1.04 (± 1.18) 0.503
RFC 0.55 (± 0.41) 0.18 (± 0.87) 0.18 (± 0.78) 0.095 0.143 –0.16 (± 1.29) –0.04 (± 1.25) 0.968
RFR 0.42 (± 0.87) 0.56 (± 0.68) 0.46 (± 0.78) 0.551 0.911 –0.31 (± 0.73) –0.57 (± 0.86) 0.090
Negative values indicate worse performances than age-matched normal population. For CMS1, CMS2, TMT-a, TMT-b, TMT b-a, instead,
Au
the higher the score, the worse the performance. p (1) indicates level of significance for comparison between SCD-s and SCD-p; p (2)
indicates level of significance for the comparisons between SCD-s and SCD-c; p (3) indicates level of significance for the comparisons
between MCI-s and MCI-c (significant differences at p < 0.05, in bold characters, underlined). SCD, subjective cognitive decline; MCI, mild
cognitive impairment; CMS, Composite Memory Scores; FWA, Five Words Acquisition; PWA, Paired Words Acquisition; BS and BSR,
Babcock Short Story Immediate and Delayed Recall; DS, Digit Span; RBMT, Rivermead Behavioral Memory Test; TMT, Trail Making Test;
DT, Dual Task; TT, Token Test; PFT, Phonemic Fluency Test; CFT, Category Fluency Task; CD, Copying Drawings; CT, Corsi Tapping
d

Test; RFC, Rey-Osterrieth Complex Figure copy; RFR, Rey-Osterrieth Complex Figure test.

significantly different at baseline between SCD-s and effect on the risk that participants would develop AD
cte

375 397

376 SCD-c, we used ROC-curve analysis to find the most (Table 5). 398

377 accurate neuropsychological tests in differentiating In the MCI group, MCI-c had worse performance at 399

378 SCD-s from SCD-c (Table 4). FW24, CMS1, and baseline compared to MCI-s on all neuropsycholog- 400

379 CMS2 provided only a sufficient prognostic accuracy. ical tests assessing long term verbal memory (FWA, 401
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380 FW24 had low sensitivity (60.0%) and low specificity FWR10, FWR24, PWR10, PWR24, BS, BSR) and on 402

381 (61.8%). CMS1 and CMS2 provided a good speci- RBMT. CMS1 and CMS2 was higher in MCI-c than 403

382 ficity (72.1% and 73.5%, respectively), but a very low in MCI-s. In the MCI group, CMS1, CMS2, RBMT, 404

383 sensitivity (60.0%). All three tests provided a very BSR, BS, and FW10 offered an acceptable accuracy 405
co

384 low PPV but a high NPV. A Cox regression analysis (Table 4). BSR offered the best sensitivity (77.3%) 406

385 was performed to evaluate the effect of FW24, CMS1, but poor specificity (65.9%). CMS1 and FW10 pro- 407

386 and CMS2 on the risk of dementia and to ascer- vided a very good specificity (78.0%), at the cost 408

387 tain if this effect is independent from age at baseline of a low sensitivity (68.2%). CMS2 and BS had a 409
Un

388 and APOE genotype. We considered these two vari- more balanced diagnostic accuracy with acceptable 410

389 ables (age at baseline and APOE), although they did sensitivity (72.7%) and specificity (73.2%, 70.7%, 411

390 not show statistically significant difference between respectively). RBMT provided the best specificity 412

391 SCD-s and SCD-c, as they are generally reported to be (80.5%), with a good sensitivity (72.7%). The other 413

392 the strongest risk factors for the development of AD tests showed lower AUC values with poorer sen- 414

393 in SCD subjects [57, 58]. The Cox regression model sitivity and specificity. Including these tests in a 415

394 was statistically significant (χ2 = 7.91, p = 0.020). Of Cox regression analysis, only CMS2 and BSR were 416

395 the neuropsychological variables included in this included in the final model corrected for APOE and 417

396 analysis, only CMS1 had a statistically significant age at baseline (χ2 = 27.093, p < 0.001) (Table 5).
V. Bessi et al. / Predicting Conversion from SCD and MCI to AD 7

Table 4
Area under the curve (AUC), cut-off values, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of
neuropsychological tests. Cut-off values are expressed as z-scores
AUC Cut-off Sensitivity (± C.I) Specificity (± C.I) PPV (± C.I) NPV (± C.I)
SCD-s versus SCD-c
CMS1 0.679 –0.93 60.0% (± 24.79) 72.1% (± 10.6) 30,61% (± 16,66) 88,81% (± 8,44)
CMS2 0.671 –0.32 60.0% (± 24.79) 73.5% (± 10.49) 33,31% (± 17,77) 89,28% (± 8,10)
FW24 0.683 0.02 60.0% (± 24.79) 61.8% (± 11.55) 25,73% (± 14,49) 87,51% (± 9,35)
MCI-s versus MCI-c

f
CMS2 0.794 –0.03 72.7% (± 13.98) 73.2% (± 10.85) 62,31% (± 14,08) 81,48% (± 10,04)

roo
RBMT 0.788 –0.93 72.7% (± 13.98) 80.5% (± 9.71) 69,44% (± 14,13) 82,87% (± 9,37)
BSR 0.785 –0.74 77.3% (± 13.15) 65.9% (± 11.61) 58,01% (± 13,42) 82,65% (± 10,39)
CMS1 0.782 –0.74 72.7% (± 13.98) 77.8% (± 10.18) 66,62% (± 14,17) 82,38% (± 9,60)
BS 0.777 –0.86 72.7% (± 13.98) 70.7% (± 11.15) 60,19% (± 13,98) 80,95% (± 10,29)
FW10 0.761 –0.05 68.2% (± 14.62) 78.0% (± 10.15) 65,39% (± 14,62) 80,10% (± 9,91)
FW24 0.739 –0.58 63.6% (± 15.19) 65.9% (± 11.61) 53,20% (± 14,32) 74,82% (± 11,33)
FWA 0.738 –0.15 68.2% (± 14.62) 61.0% (± 11.95) 51,59% (± 13,64) 75,89% (± 11,69)

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PW10 0.710 0.11 68.2% (± 14.62) 65.9% (± 11.61) 54,93% (± 14,01) 77,28% (± 11,12)
PW24 0.669 –0.58 63.6% (± 15.19) 68.3% (± 11.40) 55,01% (± 14,52) 75,49% (± 11,08)
SCD, subjective cognitive decline; MCI, mild cognitive impairment; CMS, Composite Memory Scores; FWA, Five Words Acquisition;
PWA, Paired Words Acquisition; BS and BSR, Babcock Short Story Immediate and Delayed Recall; RBMT, Rivermead Behavioral Memory
Test.

tho
418 Personality traits we investigated the effect of personality traits and 446

cognitive reserve variables in increasing or reduc- 447

419 For the analysis on personality traits and leisure ing the risk of progression to MCI in SCD subjects. 448

420 activities, 26 SCD-s and 10 SCD-p were included. To our knowledge, this is one of the first studies to 449
Au
421 Emotional stability was significantly lower in SCD-s have evaluated all these different features on the same 450

422 than in SCD-p (Table 6). A Cox regression analysis sample. 451

423 was performed to evaluate the effect of emotional sta- Among 109 SCD subjects, 26 progressed to MCI 452

424 bility on the risk of progression from SCD to MCI (SCD-p) and 15 converted to AD (SCD-c). In our 453

425 and to ascertain if this effect is independent from sample, CCP from SCD to MCI and from SCD to 454

age at baseline and APOE genotype. The Cox regres- AD is comparable to the CCP reported in a recent
d

426 455

427 sion model was statistically significant (χ2 = 16.877, meta-analysis by Mitchell et al. [10]. ACR from SCD 456

p = 0.010). Emotional Stability had a statistically sig-


cte

428 to MCI and from SCD to AD are quite low with 457

429 nificant effect on the risk that participants would respect to ACR reported in the same meta-analysis, 458

430 progress to MCI (Table 5). In particular, risk of pro- but similar to ACRs reported in studies which ana- 459

431 gression seems to be higher in subjects with a higher lyzed samples of subjects with an average age at 460

432 Emotional Stability score (hazard ratio = 1.089). baseline comparable with average age at baseline in 461
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our sample [59, 60]. Of 103 MCI subjects, 39 devel- 462

433 Leisure activities oped AD (MCI-c) with an ACR and a CCP close to 463

the data reported in the literature [59]. 464

434 No differences were found at baseline between Several prospective studies suggested that cogni- 465

SCD-s and SCD-p in the three leisure activities scores


co

435 tive deficits are detectable up to 12 years before the 466

436 (Table 6). Including them in a Cox Regression anal- clinical diagnosis of AD dementia [60–67]. In our 467

437 ysis corrected for schooling and TIB (considered sample, SCD-c subjects obtained worse scores on ver- 468

438 as cognitive reserve indexes), intellectual activities bal long-term memory tasks on average seven years 469
Un

439 resulted as protective factor, reducing the risk of con- before the diagnosis of AD, in line with other studies 470

440 version from SCD to MCI of about 30% (χ2 = 12.122, on SCD [19, 68]. On the contrary, no significant dif- 471

441 p = 0.007) (Table 5). ferences were found at baseline between SCD-s and 472

SCD-c for tests exploring other cognitive domains. 473

442 DISCUSSION In the SCD group, neuropsychological tests provided 474

only a sufficient accuracy in distinguishing convert- 475

443 We aimed to evaluate the role of neuropsychologi- ers and non-converters. In particular, as the PPVs 476

444 cal tests conducted at baseline in identifying SCD and were extremely low, neuropsychological tests did not 477

445 MCI subjects who will developed AD. Furthermore, provide useful information about SCD subjects who 478
8 V. Bessi et al. / Predicting Conversion from SCD and MCI to AD

Table 5 Our analysis has demonstrated that the effect of 500


Cox regression analysis CMS on the risk of progression to dementia is not 501

B p HR 95% CI influenced by other well-known risk factors, such as 502


lower upper
age at baseline and APOE, both in SCD and MCI 503
SCD-s versus. SCD-c subjects. Several studies used composite cognitive 504
CMS1 3.415 0.043 30.427 1.111 833.617
MCI-s versus MCI-c score to track decline better than the single most sen- 505

CMS2 1.469 0.021 4.346 1.247 15.145 sitive tests in SCD [68] and in MCI [72–74]. Our 506

BSR 1.161 0.039 3.194 0.104 0.941 and other groups’ data seem to confirm that com- 507

f
SCD-s versus SCD-p
posite cognitive scores could provide a more tailored 508

roo
Emotional stability 0.086 .013 1.089 1.019 1.165
Intellectual activities –0.357 0.007 0.700 0.540 0.907 and complete neuropsychological characterization 509

Regression coefficients (B), p-value (p), hazard ratios (HR), and than single tests in addition to a higher diagnostic 510

95% confidence intervals (95% CI) for neuropsychological tests, accuracy. 511

personality traits and leisure activities included in the regression We would like to point out that the cut-off values 512
models are reported. of neuropsychological tests we identified as distin- 513

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guishing stable subjects from converters (Table 4) 514

Table 6 are different from cut-off values adopted in clinical 515

Raw score mean values for each personality trait and leisure activ- practice to define pathological scores at neuropsy- 516

ities in SCD-s and SCD-p chological tests (i.e., 2 standard deviations under 517

tho
Personality Traits SCD-s (26) SCD-p (10) p the general population mean). In agreement with 518

Energy 42.00 (± 8.78) 45.50 (± 8.48) 0.301 other authors [75, 76], we suppose that cut-off values 519

Friendship 49.69 (± 10.99) 45.40 (± 10.45) 0.295 adopted in clinical practice are suitable for the diag- 520
Consciousness 46.00 (± 11.36) 51.10 (± 11.14) 0.234 nosis of a full-blown dementia but are not sufficiently 521
Emotional Stability 46.00 (± 11.36) 54.60 (± 11.14) 0.027
Openness 43.04 (± 9.89) 44.40 (± 12.45) 0.733 sensitive to detect those SCD and MCI patients who 522
Au
Leisure Activities will convert to AD. Several studies adopted different 523

Intellectual 16.13 (± 4.33) 14.16 (± 7.40) 0.327 cut-off values (–1 SD, –1.5 SD, –1.96 SD) to esti- 524
Social 7.38 (± 3.41) 9.10 (± 5.51) 0.263 mate the real neuropsychological test reliability in 525
Physical 4.52 (± 3.58) 6.22 (± 6.05) 0.304
predicting conversion from MCI to AD [77–79]. For 526
p indicates level of significance for the comparisons between
groups (significant differences at p < 0.05, in bold characters,
this reason, we suggest that more sensitive and more 527

specific neuropsychological cut-off values should be


d

underlined). 528

established and applied in the evaluation of SCD and 529


cte

MCI patients with the goal of earlier differentiation of 530


479 obtained scores below the cut-off values reported in converters from non-converters, rather than healthy 531
480 Table 4. However, the high NPVs may suggest that from demented subjects. 532
481 SCD subjects who obtained scores above the cut-off In a subgroup, we compared personality traits 533
482 values have a very low probability of progression between SCD-s and SCD-p subjects. We are aware 534
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483 to AD. of only three previous studies examining all domains 535
484 In line with the international literature on the topic, of the Big Five Factors Questionnaire [80–82]. As 536
485 in our sample MCI-c subjects performed worse than several studies showed that among middle-aged 537
486 MCI-s subjects on tests about verbal memory [69, and older adults, personality traits are associated 538
70] and ecological evaluation of memory [71]. In
co

487 with cognitive functioning when measured concur- 539


488 particular RBMT, an ecologically-valid memory test rently [83, 84], as a preliminary point we excluded 540
489 battery, appeared as the most accurate neuropsycho- correlations between personality traits and scores 541
490 logical test in predicting conversion from MCI to AD. in neuropsychological tests. In our sample high 542
Un

491 MCI subjects whose score at RBMT was lower than emotional stability represented a risk factor for pro- 543
492 the cut-off value reported in Table 4 had a probabil- gression from SCD to MCI. This finding is partially 544
493 ity of progressing to AD of 70%, while MCI subjects in contrast with literature data. In fact, low emotional 545
494 who resulted negative for the same test had an 80% stability has been reported as a risk factor for clin- 546
495 probability of remaining stable. This observation is ical AD and memory deficit [27, 28] and has been 547
496 confirmed by other previous studies [70, 71] and associated with a faster rate of cognitive decline [84, 548
497 could be worthy of further investigation as it could 89]. However, these studies were conducted on a 549
498 represent a simple and cost-effective tool for initial sample of aged people and not limited to SCD. Indi- 550
499 outpatient evaluations for MCI. viduals with low emotional stability respond worse 551
V. Bessi et al. / Predicting Conversion from SCD and MCI to AD 9

552 to stressors and are more likely to interpret minor However, this study has some remarkable 604

553 frustrations as hopelessly difficult, by definition, and strengths. The first is the very long, average follow- 605

554 tend to report more complaints about their memory up time. In fact, follow-up time in the SCD-s group 606

555 [90]. Thus, we suggest that in SCD subjects with is comparable to time of conversion in SCD-c, and 607

556 low emotional stability, self-reported cognitive dis- MCI-s is even much longer than conversion time in 608

557 orders could more likely represent only a subjective MCI-c. This information allows us to minimize the 609

558 complaint than a manifestation of an underlying neu- possible underestimation of conversion to AD and 610

559 rodegenerative disease. Further research is clearly the risk of classifying as stable subjects carrying an 611

f
560 needed to confirm this hypothesis. AD pathology who will convert later in the follow- 612

roo
561 The last aspect we investigated is the role of cog- up. The second strength of this study is the inclusion 613

562 nitive reserve in SCD. The Cognitive Reserve model of variables such as personality and cognitive reserve 614

563 refers to the capacity to cope with greater amounts of which complement the clinical and neuropsycholog- 615

564 cerebral damage in brighter individuals [39, 40]. In ical assessments. 616

565 AD patients, Cognitive Reserve theory predicts that In conclusion, our findings support the evidence 617

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566 the clinical manifestation of advancing AD pathology that slight differences in neuropsychological mea- 618

567 would be delayed in patients with higher expo- surements between converters and non-converters 619

568 sure to cognitive, social and physical activities [85]. to AD are detectable many years before diagno- 620

569 Furthermore, emerging evidence showed an inverse sis of dementia both in SCD and MCI. We also 621

tho
570 association between A␤ deposition and lifelong cog- demonstrate that emotional stability and intellectual 622

571 nitive activities in cognitively normal subjects [86, activities influence the risk of progression from sub- 623

572 87] suggesting that lifestyle factors such as cognitive jective to objective cognitive decline. These results 624

573 and physical activity may also have direct neuropro- suggest that memory neuropsychological tests may 625

574 tective effects. represent a reliable tool, which are easy to administer 626
Au
575 As Cognitive Reserve is a hypothetical construct, in outpatient evaluation of MCI, to estimate the risk 627

576 direct measurements of reserve are not available of progression to AD. In SCD neuropsychological 628

577 [88]. Therefore, surrogate or proxy measurements tests do not seem to be sensitive enough to dis- 629

578 are used to approach reserve. Education [89] and criminate between converters and non-converters to 630

579 engagement in leisure and cognitive activities [90] are AD. However, personality and lifestyle factors could 631

considered as standard proxies of cognitive reserve. provide useful information to identify, at an earlier
d

580 632

581 Performance-based measurements (such as vocab- stage, SCD subjects who may develop an objective 633
cte

582 ulary or reading tests) have been used as they are cognitive impairment and who should merit further 634

583 thought to show little change with age and remain investigations, such as biomarkers analysis. 635

584 relatively preserved in the early stages of dementia Future studies on larger samples, also combining 636

585 [91, 92]. neuropsychological and biological data, are needed 637

586 We considered three categories of leisure activ- to further delineate the significance of these findings. 638
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587 ities, age of schooling as education index, and


588 TIB as premorbid intelligence index. We found
ACKNOWLEDGMENTS 639
589 that Intellectual Activities could act as a protective
590 factor, reducing risk of progression from SCD to
This research was funded by Ministero della Salute 640
co

MCI by 30%. Our results are supported by several


and Regione Toscana (grants n◦ GR-2010-2316359
591
641
592 previous studies showing that participation in cog-
- Longitudinal clinical-neuropsychological study of 642
593 nitive or leisure activities [93, 94] delayed memory
subjective memory complaints). 643
594 decline.
Authors’ disclosures available online (https://
Un

644
595 The present study has some limitations. First of
www.j-alz.com/manuscript-disclosures/17-1180r2). 645
596 all, the small size of the sample and in particular
597 in the subgroup considered for the personality traits
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