Beruflich Dokumente
Kultur Dokumente
DOI 10.3233/JAD-171180
IOS Press
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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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INTRODUCTION 29
Brambilla, 3, 50134, Florence, Italy. Tel.: +39 05 7948660; Fax: tification of subjects at an early stage is crucial for 33
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
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
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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
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
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
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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
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
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
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251 Personality traits and leisure activities lations between groups’ numeric measures. We used 299
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
265 dimension.
At baseline, subjects were interviewed regarding
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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
277 Apolipoprotein E 4 genotyping subjects (2%) regressed to SCD and we included 324
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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
<0.001
<0.001
0.615
0.870
0.092
0.083
0.556
0.241
0.737
p (3)
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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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)
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41/22
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
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
11/4
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
19/7
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362 in neuropsychological tests, personality traits
363 and leisure activities between APOE 4 + and
APOE 4–.
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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-
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,
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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
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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
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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
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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)
rP
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
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
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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433 Leisure activities oped AD (MCI-c) with an ACR and a CCP close to 463
434 No differences were found at baseline between Several prospective studies suggested that cogni- 465
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
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
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
rP
guishing stable subjects from converters (Table 4) 514
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
underlined). 528
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
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
rre
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
598 and leisure activities analysis. The absence of a con- REFERENCES 646
652 decline in sporadic Alzheimer’s disease: A prospective [12] Brodaty H, Heffernan M, Kochan NA, Draper B, Trollor 717
653 cohort study. Lancet Neurol 12, 357-367. JN, Reppermund S, Slavin MJ, Sachdev PS (2013) Mild 718
654 [2] Jack CR, Knopman DS, Jagust WJ, Petersen RC, cognitive impairment in a community sample: The Sydney 719
655 Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste Memory and Ageing Study. Alzheimers Dement 9, 310- 720
656 HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue 317.e1. 721
657 MC, Trojanowski JQ (2013) Tracking pathophysiological [13] Arnáiz E, Almkvist O (2003) Neuropsychological features 722
658 processes in Alzheimer’s disease: An updated hypothet- of mild cognitive impairment and preclinical Alzheimer’s 723
659 ical model of dynamic biomarkers. Lancet Neurol 12, disease. Acta Neurol Scand Suppl 179, 34-41. 724
660 207-216. [14] Newman SK, Warrington EK, Kennedy AM, Rossor MN 725
661 [3] Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman (1994) The earliest cognitive change in a person with 726
f
662 HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen familial Alzheimer’s disease: Presymptomatic neuropsy- 727
roo
663 RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The chological features in a pedigree with familial Alzheimer’s 728
664 diagnosis of mild cognitive impairment due to Alzheimer’s disease confirmed at necropsy. J Neurol Neurosurg Psychi- 729
665 disease: Recommendations from the National Institute on atry 57, 967-972. 730
666 Aging-Alzheimer’s Association workgroups on diagnostic [15] Jacobs DM, Sano M, Dooneief G, Marder K, Bell KL, 731
667 guidelines for Alzheimer’s disease. Alzheimers Dement 7, Stern Y (1995) Neuropsychological detection and charac- 732
668 270-279. terization of preclinical Alzheimer’s disease. Neurology 45, 733
rP
669 [4] Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, 957-962. 734
670 Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park [16] Masur DM, Sliwinski M, Lipton RB, Blau AD, Crystal HA 735
671 DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, (1994) Neuropsychological prediction of dementia and the 736
672 Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, absence of dementia in healthy elderly persons. Neurology 737
673 Phelps CH (2011) Toward defining the preclinical stages of 44, 1427-1432. 738
674 Alzheimer’s disease: Recommendations from the National [17] Small BJ, Herlitz A, Fratiglioni L, Almkvist O, Bäckman 739
tho
675 Institute on Aging-Alzheimer’s Association workgroups on L (1997) Cognitive predictors of incident Alzheimer’s dis- 740
676 diagnostic guidelines for Alzheimer’s disease. Alzheimers ease: A prospective longitudinal study. Neuropsychology 11, 741
677 Dement 7, 280-292. 413-420. 742
678 [5] Brodaty H, Heffernan M, Kochan NA, Draper B, Trollor [18] Kurt P, Yener G, Oguz M (2011) Impaired digit span can 743
679 JN, Reppermund S, Slavin MJ, Sachdev PS (2013) Mild predict further cognitive decline in older people with subjec- 744
680 cognitive impairment in a community sample: The Sydney tive memory complaint: A preliminary result. Aging Ment 745
Au
681 Memory and Ageing Study. Alzheimers Dement 9, 310- Health 15, 364-369. 746
682 317.e1. [19] Silva D, Guerreiro M, Maroco J, Santana I, Rodrigues A, 747
683 [6] Jessen F, Amariglio RE, van Boxtel M, Breteler M, Cec- Bravo Marques J, de Mendonça A (2012) Comparison of 748
684 caldi M, Chételat G, Dubois B, Dufouil C, Ellis KA, van four verbal memory tests for the diagnosis and predictive 749
685 der Flier WM, Glodzik L, van Harten AC, de Leon MJ, value of mild cognitive impairment. Dement Geriatr Cogn 750
686 McHugh P, Mielke MM, Molinuevo JL, Mosconi L, Osorio Disord Extra 2, 120-131. 751
687 RS, Perrotin A, Petersen RC, Rabin LA, Rami L, Reisberg [20] Balota DA, Tse C-S, Hutchison KA, Spieler DH, Duchek 752
d
688 B, Rentz DM, Sachdev PS, de la Sayette V, Saykin AJ, JM, Morris JC (2010) Predicting conversion to dementia of 753
689 Scheltens P, Shulman MB, Slavin MJ, Sperling RA, Stew- the Alzheimer type in a healthy control sample: The power 754
cte
690 art R, Uspenskaya O, Vellas B, Visser PJ, Wagner M (2014) of errors in Stroop Color Naming. Psychol Aging 25, 208- 755
691 A conceptual framework for research on subjective cogni- 218. 756
692 tive decline in preclinical Alzheimer’s disease. Alzheimers [21] Van Mierlo LD, Wouters H, Sikkes SAM, Van der Flier 757
693 Dement 10, 844-852. WM, Prins ND, Bremer JAE, Koene T, Van Hout HPJ (2017) 758
694 [7] Perrotin A, Mormino EC, Madison CM, Hayenga AO, Screening for mild cognitive impairment and dementia with 759
695 Jagust WJ (2012) Subjective cognition and amyloid deposi- automated, anonymous online and telephone cognitive self- 760
rre
696 tion imaging: A Pittsburgh Compound B positron emission tests. J Alzheimers Dis 56, 249-259. 761
697 tomography study in normal elderly individuals. Arch Neu- [22] Crowe M, Andel R, Pedersen NL, Gatz M (2007) Do work- 762
698 rol 69, 223-229. related stress and reactivity to stress predict dementia more 763
699 [8] Amariglio RE, Becker JA, Carmasin J, Wadsworth LP, than 30 years later? Alzheimer Dis Assoc Disord 21, 205- 764
700 Lorius N, Sullivan C, Maye JE, Gidicsin C, Pepin LC, 209. 765
co
701 Sperling RA, Johnson KA, Rentz DM (2012) Subjective [23] Ausén B, Edman G, Almkvist O, Bogdanovic N 766
702 cognitive complaints and amyloid burden in cogni- (2009) Personality features in subjective cognitive 767
703 tively normal older individuals. Neuropsychologia 50, impairment and mild cognitive impairment–early indi- 768
704 2880-2886. cators of dementia? Dement Geriatr Cogn Disord 28, 769
705 [9] Stewart R, Godin O, Crivello F, Maillard P, Mazoyer B, 528-535. 770
Un
706 Tzourio C, Dufouil C (2011) Longitudinal neuroimag- [24] Kondo K, Niino M, Shido K (1994) A case-control study 771
707 ing correlates of subjective memory impairment: 4-year of Alzheimer’s disease in Japan–significance of life-styles. 772
708 prospective community study. Br J Psychiatry 198, 199-205. Dementia 5, 314-326. 773
709 [10] Mitchell AJ, Beaumont H, Ferguson D, Yadegarfar M, [25] Balestrieri M, Nacmias B, Sorbi S, Marcon G (2000) Are 774
710 Stubbs B (2014) Risk of dementia and mild cognitive premorbid personality traits linked to the risk of Alzheimer’s 775
711 impairment in older people with subjective memory com- Disease? A case series of subjects with familial mutation. 776
712 plaints: Meta-analysis. Acta Psychiatr Scand 130, 439-451. Psychother Psychosom 69, 335-338. 777
713 [11] Mendonça MD, Alves L, Bugalho P (2016) From subjec- [26] Wilson RS, Schneider JA, Arnold SE, Bienias JL, Ben- 778
714 tive cognitive complaints to dementia: Who is at risk? A nett DA (2007) Conscientiousness and the incidence of 779
715 systematic review. Am J Alzheimers Dis Other Demen 31, Alzheimer disease and mild cognitive impairment. Arch Gen 780
716 105-114. Psychiatry 64, 1204-1212. 781
V. Bessi et al. / Predicting Conversion from SCD and MCI to AD 11
782 [27] Terracciano A, Sutin AR, An Y, O’Brien RJ, Ferrucci [43] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, 847
783 L, Zonderman AB, Resnick SM (2014) Personality and Black S, Freedman M, Kertesz A, Robert PH, Albert M, 848
784 risk of Alzheimer’s disease: New data and meta-analysis. Boone K, Miller BL, Cummings J, Benson DF (1998) 849
785 Alzheimers Dement 10, 179-186. Frontotemporal lobar degeneration: A consensus on clinical 850
786 [28] Luchetti M, Terracciano A, Stephan Y, Sutin AR (2016) Per- diagnostic criteria. Neurology 51, 1546-1554. 851
787 sonality and cognitive decline in older adults: Data from a [44] Bracco L, Amaducci L, Pedone D, Bino G, Lazzaro MP, 852
788 longitudinal sample and meta-analysis. J Gerontol B Psy- Carella F, D’Antona R, Gallato R, Denes G (1990) Italian 853
789 chol Sci Soc Sci 71, 591-601. Multicentre Study on Dementia (SMID): A neuropsy- 854
790 [29] Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, chological test battery for assessing Alzheimer’s disease. 855
791 Mayeux R (1994) Influence of education and occupation J Psychiatr Res 24, 213-226. 856
f
792 on the incidence of Alzheimer’s disease. JAMA 271, 1004- [45] Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A (2002) 857
roo
793 1010. Rey-Osterrieth complex figure: Normative values in an Ital- 858
794 [30] Potter GG, Helms MJ, Plassman BL (2008) Associations of ian population sample. Neurol Sci 22, 443-447. 859
795 job demands and intelligence with cognitive performance [46] Baddeley A, Della Sala S, Papagno C, Spinnler H (1997) 860
796 among men in late life. Neurology 70, 1803-1808. Dual-task performance in dysexecutive and nondysexec- 861
797 [31] Verghese J, Lipton RB, Katz MJ, Hall CB, Derby CA, Kus- utive patients with a frontal lesion. Neuropsychology 11, 862
798 lansky G, Ambrose AF, Sliwinski M, Buschke H (2003) 187-194. 863
rP
799 Leisure activities and the risk of dementia in the elderly. [47] Spinnler H, Tognoni G (1987) Standardizzazione e taratura 864
800 N Engl J Med 348, 2508-2516. italiana di test neuropsicologici: Gruppo italiano per lo 865
801 [32] Wilson RS, Scherr PA, Schneider JA, Tang Y, Bennett DA studio neuropsicologico dell’invecchiamento, Masson Italia 866
802 (2007) Relation of cognitive activity to risk of developing Periodici, Milano. 867
803 Alzheimer disease. Neurology 69, 1911-1920. [48] Giovagnoli AR, Del Pesce M, Mascheroni S, Simoncelli M, 868
804 [33] Larson EB (2008) Physical activity for older adults at risk Laiacona M, Capitani E (1996) Trail making test: Normative 869
tho
805 for Alzheimer disease. JAMA 300, 1077-1079. values from 287 normal adult controls. Ital J Neurol Sci 17, 870
806 [34] Fratiglioni L, Paillard-Borg S, Winblad B (2004) An active 305-309. 871
807 and socially integrated lifestyle in late life might protect [49] Brazzelli M, Della Sala S, Laiacona M (1993) Calibration of 872
808 against dementia. Lancet Neurol 3, 343-353. the Italian version of the Rivermead Behavioural Memory 873
809 [35] Stern Y (2002) What is cognitive reserve? Theory and Test: A test for the ecological evaluation of memory. Boll 874
810 research application of the reserve concept. J Int Neuropsy- Psicol Appl 206, 33-42. 875
Au
811 chol Soc 8, 448-460. [50] Colombo L, Sartori G, Brivio C (2002) Stima del quoziente 876
812 [36] Scarmeas N, Albert SM, Manly JJ, Stern Y (2006) Educa- intellettivo tramite l’applicazione del TIB (Test Breve di 877
813 tion and rates of cognitive decline in incident Alzheimer’s Intelligenza). G Ital Psicol 3, 613-637. 878
814 disease. J Neurol Neurosurg Psychiatry 77, 308-316. [51] Nelson H (1982) National Adult Reading Test (NART): For 879
815 [37] Crook TH, Feher EP, Larrabee GJ (1992) Assessment of the Assessment of Premorbid Intelligence in Patients with 880
816 memory complaint in age-associated memory impairment: Dementia: Test Manual, Windsor, UK. 881
817 The MAC-Q. Int Psychogeriatr 4, 165-176. [52] Hamilton M (1960) A rating scale for depression. J Neurol 882
d
818 [38] Lawton MP, Brody EM (1969) Assessment of older people: Neurosurg Psychiatry 23, 56-62. 883
819 Self-maintaining and instrumental activities of daily living. [53] Goldberg LR (1992) The development of markers for the 884
cte
820 Gerontologist 9, 179-186. Big-Five factor structure. Psychol Assess 4, 26-42. 885
821 [39] Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, [54] Costa PT, McCrae RR (1985) The NEO personality inven- 886
822 Wahlund L-O, Nordberg A, Bäckman L, Albert M, Almkvist tory: Manual, form S and form R, Psychological Assessment 887
823 O, Arai H, Basun H, Blennow K, De Leon M, DeCarli Resources. 888
824 C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, [55] Yarnold PR, Stille FC, Martin GJ (1995) Cross-sectional 889
825 Jorm A, Ritchie K, Van Duijn C, Visser P, Petersen RC psychometric assessment of the Functional Status Ques- 890
rre
826 (2004) Mild cognitive impairment - beyond controversies, tionnaire: Use with geriatric versus nongeriatric ambulatory 891
827 towards a consensus: Report of the International Working medical patients. Int J Psychiatry Med 25, 305-317. 892
828 Group on Mild Cognitive Impairment. J Intern Med 256, [56] Sorbi S, Nacmias B, Forleo P, Latorraca S, Gobbini I, Bracco 893
829 240-246. L, Piacentini S, Amaducci L (1994) ApoE allele frequen- 894
830 [40] McKhann GM, Knopman DS, Chertkow H, Hyman BT, cies in Italian sporadic and familial Alzheimer’s disease. 895
co
831 Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly Neurosci Lett 177, 100-102. 896
832 JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Schel- [57] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, 897
833 tens P, Carrillo MC, Thies B, Weintraub S, Phelps CH Gaskell PC, Small GW, Roses AD, Haines JL, Pericak- 898
834 (2011) The diagnosis of dementia due to Alzheimer’s dis- Vance MA (1993) Gene dose of apolipoprotein E type 4 899
835 ease: Recommendations from the National Institute on allele and the risk of Alzheimer’s disease in late onset fam- 900
Un
836 Aging-Alzheimer’s Association workgroups on diagnostic ilies. Science 261, 921-923. 901
837 guidelines for Alzheimer’s disease. Alzheimers Dement 7, [58] Guerreiro R, Bras J (2015) The age factor in Alzheimer’s 902
838 263-269. disease. Genome Med 7, 106. 903
839 [41] Quach C, Hommet C, Mondon K, Lauvin MA, Cazals X, [59] Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos 904
840 Cottier JP (2014) Early-onset dementias: Specific etiologies EG, Kokmen E (1999) Mild cognitive impairment: Clinical 905
841 and contribution of MRI. Diagn Interv Imaging 95, 377-398. characterization and outcome. Arch Neurol 56, 303-308. 906
842 [42] Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, [60] Amieva H, Jacqmin-Gadda H, Orgogozo J-M, Le Carret N, 907
843 Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun Helmer C, Letenneur L, Barberger-Gateau P, Fabrigoule C, 908
844 A, Hofman A (1993) Vascular dementia: Diagnostic cri- Dartigues J-F (2005) The 9 year cognitive decline before 909
845 teria for research studies. Report of the NINDS-AIREN dementia of the Alzheimer type: A prospective population- 910
846 International Workshop. Neurology 43, 250-260. based study. Brain 128, 1093-1101. 911
12 V. Bessi et al. / Predicting Conversion from SCD and MCI to AD
912 [61] Johnson DK, Storandt M, Morris JC, Galvin JE (2009) [75] Christa Maree Stephan B, Minett T, Pagett E, Siervo M, 977
913 Longitudinal study of the transition from healthy aging to Brayne C, McKeith IG (2013) Diagnosing mild cognitive 978
914 Alzheimer disease. Arch Neurol 66, 1254-1259. impairment (MCI) in clinical trials: A systematic review. 979
915 [62] Small BJ, Bäckman L (2007) Longitudinal trajectories BMJ Open 3, e001909. 980
916 of cognitive change in preclinical Alzheimer’s disease: A [76] Jak AJ, Bondi MW, Delano-Wood L, Wierenga C, Corey- 981
917 growth mixture modeling analysis. Cortex 43, 826-834. Bloom J, Salmon DP, Delis DC (2009) Quantification of five 982
918 [63] Grober E, Hall CB, Lipton RB, Zonderman AB, Resnick neuropsychological approaches to defining mild cognitive 983
919 SM, Kawas C (2008) Memory impairment, executive dys- impairment. Am J Geriatr Psychiatry 17, 368-375. 984
920 function, and intellectual decline in preclinical Alzheimer’s [77] Bickel H, Mosch E, Seigerschmidt E, Siemen M, Forstl H 985
921 disease. J Int Neuropsychol Soc 14, 266-278. (2006) Prevalence and persistence of mild cognitive impair- 986
f
922 [64] Howieson DB, Carlson NE, Moore MM, Wasserman D, ment among elderly patients in general hospitals. Dement 987
roo
923 Abendroth CD, Payne-Murphy J, Kaye JA (2008) Trajec- Geriatr Cogn Disord 21, 242-250. 988
924 tory of mild cognitive impairment onset. J Int Neuropsychol [78] Busse A, Hensel A, Gühne U, Angermeyer MC, Riedel- 989
925 Soc 14, 192-198. Heller SG (2006) Mild cognitive impairment: Long-term 990
926 [65] Wilson RS, Leurgans SE, Boyle PA, Bennett DA (2011) course of four clinical subtypes. Neurology 67, 2176-2185. 991
927 Cognitive decline in prodromal Alzheimer disease and mild [79] Zanetti M, Ballabio C, Abbate C, Cutaia C, Vergani C, 992
928 cognitive impairment. Arch Neurol 68, 351-356. Bergamaschini L (2006) Mild cognitive impairment sub- 993
rP
929 [66] Amieva H, Le Goff M, Millet X, Orgogozo JM, Pérès K, types and vascular dementia in community-dwelling elderly 994
930 Barberger-Gateau P, Jacqmin-Gadda H, Dartigues JF (2008) people: A 3-year follow-up study. J Am Geriatr Soc 54, 995
931 Prodromal Alzheimer’s disease: Successive emergence of 580-586. 996
932 the clinical symptoms. Ann Neurol 64, 492-498. [80] Wilson RS, Krueger KR, Arnold SE, Schneider JA, Kelly JF, 997
933 [67] Elias MF, Beiser A, Wolf PA, Au R, White RF, D’Agostino Barnes LL, Tang Y, Bennett DA (2007) Loneliness and risk 998
934 RB (2000) The preclinical phase of alzheimer disease: A of Alzheimer disease. Arch Gen Psychiatry 64, 234-240. 999
tho
935 22-year prospective study of the Framingham Cohort. Arch [81] Duberstein PR, Chapman BP, Tindle HA, Sink KM, 1000
936 Neurol 57, 808-813. Bamonti P, Robbins J, Jerant AF, Franks P (2011) Personal- 1001
937 [68] Chary E, Amieva H, Pérès K, Orgogozo J-M, Dartigues ity and risk for Alzheimer’s disease in adults 72 years of age 1002
938 J-F, Jacqmin-Gadda H (2013) Short- versus long-term pre- and older: A 6-year follow-up. Psychol Aging 26, 351-362. 1003
939 diction of dementia among subjects with low and high [82] Hock RS, Lee HB, Bienvenu OJ, Nestadt G, Samuels JF, 1004
940 educational levels. Alzheimers Dement 9, 562-571. Parisi JM, Costa PT, Spira AP (2014) Personality and cog- 1005
Au
941 [69] Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen nitive decline in the Baltimore Epidemiologic Catchment 1006
942 PS, Bennett DA, Foster NL, Jack CR, Galasko DR, Doody Area follow-up study. Am J Geriatr Psychiatry 22, 917-925. 1007
943 R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, [83] Aiken-Morgan AT, Bichsel J, Allaire JC, Savla J, Edwards 1008
944 Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer CL, Whitfield KE (2012) Personality as a source of 1009
945 J, Zamrini EY, Cahn-Weiner D, Thal LJ, Alzheimer’s Dis- individual differences in cognition among older African 1010
946 ease Cooperative Study (2004) Mild cognitive impairment Americans. J Res Personal 46, 465-471. 1011
947 can be distinguished from Alzheimer disease and normal [84] Williams P, Suchy Y, Kraybill M (2013) Preliminary evi- 1012
d
948 aging for clinical trials. Arch Neurol 61, 59-66. dence for low openness to experience as a pre-clinical 1013
949 [70] Bolló-Gasol S, Piñol-Ripoll G, Cejudo-Bolivar JC, marker of incipient cognitive decline in older adults. J Res 1014
cte
956 conversion from mild cognitive impairment to Alzheimer’s pathology, and cognition in cognitively normal older adults. 1021
957 disease. Alzheimers Dement 7, S253. Neurobiol Aging 35, 1873-1882. 1022
958 [72] Mazzeo S, Santangelo R, Bernasconi MP, Cecchetti G, Fior- [87] Landau SM, Marks SM, Mormino EC, Rabinovici GD, Oh 1023
959 ino A, Pinto P, Passerini G, Falautano M, Comi G, Magnani H, O’Neil JP, Wilson RS, Jagust WJ (2012) Association of 1024
960 G (2016) Combining cerebrospinal fluid biomarkers and lifetime cognitive engagement and low -amyloid deposi- 1025
co
961 neuropsychological assessment: A simple and cost-effective tion. Arch Neurol 69, 623-629. 1026
962 algorithm to predict the progression from mild cognitive [88] Jones RN, Manly J, Glymour MM, Rentz DM, Jefferson AL, 1027
963 impairment to Alzheimer’s disease dementia. J Alzheimers Stern Y (2011) Conceptual and measurement challenges in 1028
964 Dis 54, 1495-1508. research on cognitive reserve. J Int Neuropsychol Soc 17, 1029
965 [73] Paajanen T, Hanninen T, Tunnard C, Hallikainen M, 593-601. 1030
Un
966 Mecocci P, Sobow T, Tsolaki M, Vellas B, Lovestone S, [89] Stern Y, Alexander GE, Prohovnik I, Mayeux R (1992) 1031
967 Soininen H (2011) CERAD memory composite score is Inverse relationship between education and parietotempo- 1032
968 an accurate neuropsychological predictor of progression ral perfusion deficit in Alzheimer’s disease. Ann Neurol 32, 1033
969 to Alzheimer’s disease: AddNeuroMed study. Alzheimers 371-375. 1034
970 Dement 7, S259. [90] Scarmeas N, Levy G, Tang M-X, Manly J, Stern Y (2001) 1035
971 [74] Crane PK, Carle A, Gibbons LE, Insel P, Mackin RS, Gross Influence of leisure activity on the incidence of Alzheimer’s 1036
972 A, Jones RN, Mukherjee S, Curtis SM, Harvey D, Weiner disease. Neurology 57, 2236-2242. 1037
973 M, Mungas D (2012) Development and assessment of a [91] Park DC, Lautenschlager G, Hedden T, Davidson NS, Smith 1038
974 composite score for memory in the Alzheimer’s Disease AD, Smith PK (2002) Models of visuospatial and verbal 1039
975 Neuroimaging Initiative (ADNI). Brain Imaging Behav 6, memory across the adult life span. Psychol Aging 17, 299- 1040
976 502-516. 320. 1041
V. Bessi et al. / Predicting Conversion from SCD and MCI to AD 13
1042 [92] Wisdom NM, Mignogna J, Collins RL (2012) Variability in [94] Hall CB, Lipton RB, Sliwinski M, Katz MJ, Derby CA, 1048
1043 Wechsler Adult Intelligence Scale-IV subtest performance Verghese J (2009) Cognitive activities delay onset of mem- 1049
1044 across age. Arch Clin Neuropsychol 27, 389-397. ory decline in persons who develop dementia. Neurology 1050
1045 [93] Helzner EP, Scarmeas N, Cosentino S, Portet F, Stern Y 73, 356-361. 1051
1046 (2007) Leisure activity and cognitive decline in incident
1047 Alzheimer disease. Arch Neurol 64, 1749-1754.
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