The association of serum oestradiol level, age, and education with cognitive performance in peri- and late postmenopausal women

Maturitas 71 (2012) 173–179

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The association of serum oestradiol level, age, and education with cognitive performance in peri- and late postmenopausal women Hanna Tuomisto a , Paula Salo a , Reetta Saarinen a , Nea Kalleinen a , Päivi Polo-Kantola a,b,∗ a b

Department of Physiology (Sleep Research Unit), University of Turku, Turku, Finland Department of Obstetrics and Gynaecology, Turku University Central Hospital, Turku, Finland

a r t i c l e

i n f o

Article history: Received 22 June 2011 Received in revised form 26 November 2011 Accepted 30 November 2011

Keywords: Cognition Oestrogen Education Age Menopause Woman

a b s t r a c t Objectives: To evaluate whether healthy women show cognitive changes after menopause and whether the possible changes are oestrogen-, age- or education-dependent. Methods: Forty-eight women, 21 perimenopausal (aged 43–51 years) and 27 late postmenopausal (aged 59–71 years), participated in the study. Verbal and visuomotor functions, visuoconstructive skills, visual and verbal episodic memory as well as attention were evaluated. Results: Perimenopausal women performed better than postmenopausal women. Serum oestradiol (E2 ) level was included in the model in perimenopausal women only given the lack of endogenous oestrogen in postmenopausal women who were also not using hormone therapy (HT). In perimenopausal women, lower E2 was associated with better visual episodic memory (p < .05), and older age was related to poorer verbal episodic memory (p < .05). In postmenopausal women, more education was associated with better performance in verbal and visuomotor functions, attention as well as verbal episodic memory (p < .05), older age was related to poorer performance in the visuoconstructive test and visual episodic memory (p < .05). Conclusions: Perimenopausal women had better cognitive performance compared to late postmenopausal women. In perimenopausal women the effect of E2 was minor. In both groups, age modified cognitive performance, but more so in postmenopausal women. Education did not have any effect on cognitive performance in perimenopausal women, whereas in postmenopausal women education exceeded age as a source of variation. Thus the relevance of education for better cognition was accentuated after menopause. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Around and after menopause women frequently report increasing cognitive difficulties, especially problems with memory and concentration [1,2]. A recent study of neuropsychological cognitive measures associated with menopause suggested that cognitive difficulties would be time-limited to perimenopause only and relieve soon in postmenopause [3]. There is evidence that higher endogenous oestradiol levels are associated with better cognitive performance in selected functions in older women [4]. Since oestrogen receptors are widely distributed in the brain and oestrogen is involved in the regulation of neurotransmitters essential for cognitive functioning [5], it is possible that endogenous oestrogen

∗ Corresponding author at: Department of Obstetrics and Gynaecology, Turku University Central Hospital, Turku, Finland. Tel.: +358 2 313 000; fax: +358 2 313 2340. E-mail address: paivi.polo@tyks.fi (P. Polo-Kantola). 0378-5122/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2011.11.025

levels play an important role in cognitive performance around the menopausal transition. Previous studies have shown an age-related decline in cognitive processing speed and working memory [6,7], episodic memory [8], executive functions and attention [9], verbal performance [10], as well as in cognitive plasticity [11]. The adverse changes seem to begin slowly after the fifth decade of life [12]. On the other hand, some cognitive functions, including vocabulary and abstract knowledge, are considered to remain relatively intact even until very old age [13]. In ageing, several neuroanatomical and physiological changes occur in the brain, such as cortical atrophy [14] and deteriorations in neurotransmission [15]. Contrary to a previously held view, no significant loss of neurons seems to take place in the ageing brain [16]. Instead, a decline of brain white matter volume may account for most of the normal cognitive ageing changes [16]. Education has been shown to improve cognitive abilities like attention, memory, and executive functions [17–19]. In several studies, longer education is related to better cognitive test performance in healthy elderly [20,21]. Longer education has also been associated with lower risk of mild cognitive impairment [22] and

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Table 1 Background variables. Perimenopausal

Age (years) Education (years) Mood (BDI) Cognitive impairment (MMSE) Quality of life (EQ-5D) State of health (EQ, VAS) FSH (IU/l) E2 (pmol/l) Age at menopause (years, n = 24) Time since menopause (years, n = 24)

Postmenopausal

t-Value

Mean

SD

Mean

SD

47.7 16.6 4.3 27.9 7.2 83.3 10.4 87.7 – –

2.3 4.3 3.3 1.6 .9 10.6 4.8 87.9 – –

63.8 12.4 5.9 27.3 7.4 78.7 72.7 <7.9 50.1 13.3

3.8 3.7 3.9 1.9 .8 13.7 23.3 2.7 3.2 4.8

−17.2*** 3** −1.5** 1.2 −.9 1.3 −12.0*** 9.4*** – –

Note: BDI, Beck Depression Inventory; MMSE, Mini-Mental State Examination; EQ-5D, Euro Quality of Life-questionnaire; VAS, Visual Analog Scale. ** p < .01. *** p < .001.

dementia [23]. This beneficial effect can be due to cognitive reserve, which might protect the brain by providing either a higher threshold for neural damage or alternative ways to compensate for the adverse changes [24]. In the present study, we aimed to explore cognitive performance around the menopausal transition, including an evaluation of the potential contribution of age and education, by comparing the performance of perimenopausal women to that of late postmenopausal women.

2. Materials and methods 2.1. Participants Forty-eight women were enrolled in the study through newspaper advertisements, 21 of which were perimenopausal (age range 43–51 years) and 27 late postmenopausal (age range 59–71 years). Exclusion criteria included history of neurological disorders, severe cardiovascular (controlled hypertension was accepted), endocrinological, or mental disease, previously diagnosed and treated sleep disorders, ongoing malignancies, and abuse of alcohol or medications. Women were excluded also if they were using antipsychotics or sleeping pills. In case of previous use of hormone therapy (HT), the women were accepted only if at least 12 months had passed since the end of treatment. All women were non-smokers. Before the study, blood haemoglobin, leukocytes, thrombocytes, serum thyrotropin and free thyroxin were measured, urine drug screen was carried out, and all women with abnormalities were excluded. In women aged 43–51 years, serum follicle stimulating hormone (FSH) below 25 IU/l and ongoing menstrual cycle confirmed the perimenopausal state, whereas postmenopausal women were defined by FSH, age and amenorrhoea. The basic characteristics of the groups are shown in Table 1. Signed informed consent was obtained for participation in this study which had approval from the Ethics Committee of Turku University Central Hospital. Initial screening included global cognitive functioning evaluated with the Mini-Mental State Examination (MMSE) [25] and symptoms of depression with the Beck Depression Inventory (BDI) [26]. In the study groups, no clinically significant cognitive impairment or depression was observed (Table 1). The Euro Quality of Life-questionnaire (EQ-5D) [27] was used for evaluating subjective quality of life. Subjective state of health was measured using Visual Analog Scale (VAS) of EQ-5D. Regarding quality of life and state of heath, the groups were similar (Table 1). On the morning of the day of cognitive testing, blood samples for serum oestradiol (E2 : Spectria® RIA, Orion Diagnostica, Finland) and FSH (Delfia® TR-IFMA, Wallac, Finland) measures were obtained (Table 1). The analytical range of FSH was .2–256 IU/l and the lower limits of

detection for oestradiol 6.8 pg/l. The intra- and interassay coefficients of variation for the FSH and oestradiol were as follows: for FSH intra-assay CV 3.0% (1.5 U/l), 3.8% (5.0 U/l), 4.8% (50.2 U/l) and interassay CV 4.2% (1.5 U/l), 4.3% (5.4 U/l), 3.7% (53.4 U/l) and for oestradiol intra-assay CV 9.7% (17.7 pg/l), 7.3% (149.0 pg/l), 3.2% (427.4 pg/l), 2.9% (1436.6 pg/l) and interassay CV 10.2% (17.7 pg/l), 5.1% (107.3 pg/l), 2.3% (886.4 pg/l) and 8.3% (2593.2 pg/l). 2.2. Cognitive measurements Cognitive measurements consisted of tests evaluating verbal functions, visuomotor functions, visuoconstructive skills, visual and verbal episodic memory and attention. The tests were carried out in a quiet room between 8:00 and 11:00 a.m. All perimenopausal women were tested in the follicular phase of their menstrual cycle, as a rule between the days 2 and 7 (in two cases in day 10). 2.2.1. Verbal functions Two verbal tests, the Similarities and the Digit Span (Wechsler Adult Intelligence Scale-Revised, WAIS-R) [28], were used to measure verbal functions. The test of Similarities puts demands on conceptual knowledge, semantic memory, and abstract reasoning. The test of Digit Span is used to measure verbal working memory and attention. 2.2.2. Visuomotor functions and visuoconstructive skills To measure visuomotor functions and visuomotor skills two tests, the Digit Symbol and the Block Design, were used. The Digit Symbol is a test of visuomotor speed (WAIS-R) [28]. In the Block Design, visuoconstructive skill is evaluated (WAIS-R) [28]. 2.2.3. Episodic memory The modified version of the Rey auditory verbal learning test (RAVL) [29] was used to test verbal episodic memory. First, a list of 15 words (list A1–3) is read aloud to the subject. Thereafter, the subject has to repeat in free order as many words as she could remember. The same list is repeated three times, after which a new list (list B) of 15 words is presented with the same instructions. The purpose of the list B is to prevent rehearsal of the list A in working memory. The subject is then asked to recite as many words as possible from the list A (immediate recall = list AI). Delayed recall of the list A was asked after 20–30 min (list A, delayed recall = list AD). The Benton visual retention (BVR, form C) [30] is a test of visual episodic memory. It consists of ten cards, each including 1–3 geometric figures. The cards are presented one at a time for 10 s and after each card the subject is asked to recall it from memory

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(immediate recall). As a delayed recall after each two consecutive cards, the subject is asked to draw them again in the same order they were presented [31]. The number of errors was reported. 2.2.4. Attention The Paced Auditory Serial Addition Test (PASAT) is a measure of auditory attention. The subject is instructed to listen to single digits presented at 3 s (easy form) or 2 s (difficult form) intervals and add every two consecutive digits. The numbers of correct, erroneous, and missing answers were recorded [32]. The CogniSpeed© software measures controlled cognitive processing (described more in details elsewhere [33]). The software consists of a series of tasks, which become gradually more difficult. The three first tests (the Simple Reaction Time [SRT], the Two-Choice Reaction Time [2-CRT] and the Ten-Choice Reaction Time [10-CRT]) require quick preparation to react. The Subtraction test calls for concentrating attention and working memory, while in the Verification test attention has to be shared between working memory and simultaneous decision-making. The Vigilance task with visual stimuli is a monotonous test of sustaining attention, lasting 15 min. The CogniSpeed version of the Stroop colour-word test [34] studies suppressing attention. The colour-meaning is in congruence (Stroop congruence test) or in incongruence (Stroop incongruence tests). For all the CogniSpeed tests, median reaction times of all the trials in each test were reported. The Bourdon–Wiersma-test measures visual attention. The subject is instructed to find the targets (group of four dots among groups of the three, four or five dots) on a sheet of paper as quickly as possible. The task lasted 1 min and was repeated. For each correct answer, one point was given and for each erroneous answer, one point was subtracted. The total score is the sum of the two trials. Shared attention was measured by counting backwards. The subject was given a 3-digit number and asked to start counting backwards in steps of one-minute. The task was carried out twice. The total score is counted in a similar manner as in the Bourdon–Wiersma-test. Shared attention was assessed by using a dual task. The subject performed the Bourdon–Wiersma-test and the task of counting backwards at the same time. The one-minute test was carried out twice. Once again, the subject was instructed to perform as quickly and accurately as possible and divide her attention between both parts of the test. In order to measure the deteriorating effect of the dual task on performance, the efficiency percentage was calculated for both tasks using the following formula: dual task score/single task score × 100 = percentage dual task efficiency. 2.3. Statistical analyses Logarithm transformation was used for variables with skewed distributions (Digit Span backward, BVR immediate recall, RAVL list B, PASAT easy errors and missing, 10-CRT, Subtraction, Vigilance, Stroop congruence, Stroop incongruence, and E2 ). The differences between the peri- and postmenopausal groups were analysed using the independent samples t-test. Pearson correlation coefficients were calculated to evaluate the association of age and education with cognitive performance. Serum E2 level was also investigated, but it was only included in the analyses in the perimenopausal women. In postmenopausal women, the serum E2 levels were extremely low and distribution was severely skewed even after logarithm transformation and thus E2 level could not be included in the analyses. Multivariate regression analyses using enter method was also carried out. The model included age, education, and E2 level in perimenopausal women, and age and education in postmenopausal women. There was no collinearity between the explaining variables.

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An additional analysis among postmenopausal women was conducted to assess the relationship between the age at menopause and cognitive performance as well as the time since menopause and cognitive performance. Data of the age at menopause was incomplete, and thus 24 postmenopausal women were included (Table 1) in the multivariate regression analysis (enter method) in which either age at menopause or time since menopause was added in the model containing age and education. In all analyses, p-values less than .05 were considered significant. In the power calculations with the significance level of 5% and power 80%, the group sizes varied between n = 10 (2-CRT) to n = 24 (Bourdon–Wiersma). The analyses were performed using SPSS for Windows Version 11.0 (SPSS Inc., Chicago, USA). 3. Results 3.1. Perimenopausal vs. postmenopausal women Perimenopausal women showed better performance in the tests of visuomotor functions (Block Design and Digit Symbol) as well as visual episodic memory (BVR; Table 2). In both immediate and delayed recall in the BVR, perimenopausal women made fewer errors than postmenopausal women. Perimenopausal women performed better also in several attentional measurements, including PASAT difficult (correct and missing answers), in all but one CogniSpeed tasks on controlled cognitive processing and attention, Bourdon–Wiersma, and counting backwards during the dual task. No differences were observed in verbal functions, or verbal episodic memory. 3.2. Perimenopausal women In perimenopausal women, older age was associated with poorer performance in the test of verbal episodic memory (RAVL, list A2 and list A immediate recall), but also faster performance in the 2-CRT. Higher E2 levels were only associated with greater number of errors in the BVR (delayed), a task of visual episodic memory, but not with performance in any other tests. Length of education was not associated with performance in the tests studied (Table 3). In linear regression analyses, age explained performance in 3/6 variables in RAVL (list A2 ˇ = −.57, p = .009, list A immediate ˇ = −.54, p = .014 and list A delayed ˇ = −.45, p = .025). The model fitted the data (list A2 F3,17 = 3.72, p = .032, list A immediate F3,17 = 3.05, p = .057 and list A delayed F3,17 = 4.72, p = .14) and explained 29%, 24% and 36% of the variation, respectively. Education explained performance in RAVL list A delayed (ˇ = −.46, p = .020) and in BVR in immediate recall errors (ˇ = −.49, p = .024). E2 explained performance in BVR (immediate errors ˇ = .49, p = .024; delayed errors ˇ = .54, p = .014). The models fitted the data (BVR immediate errors F3,16 = 3.68, p = .035 and delayed errors F3,16 = 3.53, p = .039) and explained 30% and 29% of the variation, respectively. Taken together the two analyses (Pearson correlation coefficients and multivariate regression analyses) the results in perimenopausal women changed in 5/93 variables. 3.3. Postmenopausal women In postmenopausal women, age was associated with reduced performance in visuomotor functions, verbal and visual episodic memory, and attention, but not in verbal functions (Table 3). The older the women, the poorer they scored in the Block Design and the more errors they made in the BVR (both immediate and delayed). In the RAVL, older age was associated with fewer recalled words from the list A in the second trial (list A2) and from the list B. In the attention tests, older age associated with fewer correct responses

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Table 2 Performance scores in the groups. Cognitive performance

Perimenopausal Mean

Verbal functions (correct) Similarities Digit Span Forward Backward Visuomotor functions (correct) Block Design Digit Symbol Verbal episodic memory (correct) RAVL List A1 List A2 List A3 List B List A immediate recall List A delayed recall Visual episodic memory BVR immediate errors BVR delayed errors Attention PASAT Easy Correct Errors Missing Difficult Correct Errors Missing CogniSpeed (ms) SRT 2-CRT 10-CRT Subtraction Verification Vigilance Stroop congruence Stroop incongruence Bourdon–Wiersma Counting backwards Dual task Bourdon–Wiersma % Counting backwards %

Postmenopausal SD

Mean

t-Value SD

28.0

3.4

27.0

4.4

.87

6.3 6.2

1.6 1.8

6.2 6.0

1.6 1.5

.14 .31

30.0 54.7

9.8 8.7

22.4 42.1

8.7 10.4

7.6 10.3 11.9 6.7 8.9 9.0

1.8 2.3 1.7 2.1 2.8 2.5

6.7 10.1 11.9 5.9 7.7 8.5

1.5 2.1 1.9 2.3 2.8 3.0

1.97 .21 .01 1.37 1.39 .61

3.4 6.9

2.0 3.1

6.6 10.0

2.3 3.7

−4.16*** −3.06**

45.0 4.6 10.5

10.9 3.5 9.6

38.5 4.8 16.5

13.4 3.9 11.8

1.78 −.40 −1.13

35.9 4.0 20.1

10.1 2.9 9.8

27.9 4.1 27.6

11.0 2.1 10.7

2.49* −.19 −2.36*

290 448 795 1122 1252 519 491 585 68.1 85.0

33 59 120 172 305 59 71 160 11.3 12.6

317 529 986 1505 1724 547 567 743 58.3 77.3

46 74 156 413 571 69 108 278 12.0 16.6

60.3 65.3

11.2 10.6

60.0 56.7

13.2 11.8

2.83** 4.45***

−2.32* −4.11*** −4.79*** −4.40*** −3.42** −1.56 −2.88** −2.52* 2.91** 1.76 .10 2.59*

Note: BVR, Benton visual retention test; RAVL, Rey auditory verbal learning test; PASAT, Paced Auditory Serial Addition Test; SRT, Simple Reaction Time; 2-CRT, Two-Choice Reaction Time; 10-CRT, Ten-Choice Reaction Time. * p < .05. ** p < .01. *** p < .001.

and more missing responses in the PASAT easy and more missing responses in the PASAT difficult. Also in the Bourdon–Wiersma test, older age associated with worse performance. In linear regression analyses, age explained performance in Block Design (ˇ = −.45, p = .014, F2,24 = 6.95, p = .004, explanation of variation 31%) and in BVR (errors immediate ˇ = −.46, p = .018, F2,24 = 4.66, p = .019, explanation of variation 22% and errors delayed ˇ = −.49, p = .016, F2,23 = 4.64, p = .020, explanation of variation 23%). Further, age explained performance in PASAT easy correct responses (ˇ = −.39, p = .042, F2,22 = 5.55, p = .011, explanation of variation 28%) and missing responses (ˇ = .46, p = .049, F2,18 = 9.62, p = .001, explanation of variation 44%) as well as PASAT difficult missing responses (ˇ = .42, p = .010, F2,20 = 4.04, p = .035, explanation of variation 23%). Education explained performance in tests of verbal and visuomotor functions, verbal episodic memory, and attention, but not in visual episodic memory in postmenopausal women (Table 3). In the verbal tests, longer education was associated with better performance in the Similarities, Digit Span backward, and in the test of verbal episodic memory (RAVL), with more recalled words from

the list A in the second and third trials as well as in immediate recall. Longer education was also associated with better performance in the Block Design and the Digit Symbol, measures of visuomotor function. According to linear regression analyses, education explained cognitive performance in the Similarities (ˇ = .51, p = .012, F2,24 = 3.72, p = .039, explanation of variation 17%) and in the Digit Span backward (ˇ = .42, p = .035 F2,24 = 3.63, p = .042, explanation of variation 17%). Moreover, education explained cognitive performance in 3/6 variables in RAVL (list A2 ˇ = .53, p = .003; list A3 ˇ = .64, p = .001 and list A immediate ˇ = .44, p = .030). The models fitted the data (list A2 F2,24 = 8.69, p = .001; list A3 F2,24 = 9.54, p = .001 and list A immediate F2,23 = 3.00, p = .069). The models explained 37%, 40% and 14% of the variation, respectively. Also in the Digit Symbol education explained performance (ˇ = .49, p = .013, F2,24 = 4.65, p = .020, explanation of variation 22%). In attention tests, the longer the education, the better were the scores in all variables of the PASAT easy. In PASAT difficult no association was found. In the CogniSpeed tasks, longer education associated with faster reaction times in all but two subtests, namely not in SRT or Vigilance. In both the Bourdon–Wiersma and the

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Table 3 Correlation between cognitive performance and age, education and E2 . Cognitive performance

Perimenopausal Age r

Verbal functions (correct) Similarities Digit Span Forward Backward Visuomotor functions (correct) Block Design Digit Symbol Verbal episodic memory (correct) RAVL List A1 List A2 List A3 List B List A immediate recall List A delayed recall Visual episodic memory BVR Immediate errors BVR Delayed errors Attention PASAT Easy Correct Errors Missing Difficult Correct Errors Missing CogniSpeed SRT 2-CRT 10-CRT Subtraction Verification Vigilance Stroop congruence Stroop incongruence Bourdon–Wiersma Counting backwards Dual task Bourdon–Wiersma % Counting backwards %

Postmenopausal Education r

E2 r

Age r

Education r

.21

.19

−.34

−.02

.47*

.19 −.32

.16 .37

.40 −.10

−.20 −.27

.35 .46*

−.15 −.07

.36 −.07

.01 .05

−.54** −.25

.43* .52*

−.22 −.51* −.32 −.42 −.49* −.35

.34 .29 .37 −.03 .12 .40

.20 −.01 .08 .35 −.22 −.31

−.38 −.41* −.27 −.42* −.15 −.25

.31 .60** .66** .38 .45* .37

−.01 −.06

−.41 −.33

−.10 −.16 .09

.15 .27 −.13

.12 .11 −.17

−.47* .33 .54**

.44* −.54** .47*

−.02 .07 −.00

.26 −.05 −.26

.07 .08 −.10

−.35 −.25 .49*

.37 −.43 −.37

−.31 −.44* −.21 .12 −.12 −.39 −.40 −.20 −.11 −.08

.04 .02 .14 .19 −.20 .04 −.16 .08 .11 .08

−.04 .03 .20 .34 −.38 .17 −.16 −.17 .03 .13

.20 .15 .23 .04 .27 .31 .01 .16 −.40* −.15

−.23 −.44* −.44* −.60** −.51** −.12 −.43* −.46* .56** .56**

.02 −.05

−.02 −.13

−.19 −.07

−.06 −.22

.17 .19

.42 .53*

.51** .53**

−.29 −.28

Note: BVR, Benton visual retention test; RAVL, Rey auditory verbal learning test; PASAT, Paced Auditory Serial Addition Test; SRT, Simple Reaction Time; 2-CRT, Two-Choice Reaction Time; 10-CRT, Ten-Choice Reaction Time. * p < .05. ** p < .01. ***p < .001.

counting backwards task, longer education associated with better scores. In linear regression analyses, education explained cognitive performance in the PASAT easy missing responses (ˇ = −.46, p = .010, F2,20 = 9.62, p = .001, explanation of variation 44%) and in PASAT difficult errors (ˇ = −.51, p = .019, F2,18 = 4.10, p = .034, explanation of variation 24%). Further, education explained performance in 2-CRT (ˇ = −.43, p = .033, F2,24 = 2.89, p = .075, explanation of variation 13%), 10-CRT (ˇ = −.40, p = .044, F2,24 = 3.06, p = .066 explanation of variation 14%), Subtraction (ˇ = −.64, p = .001, F2,24 = 7.23, p = .003, explanation of variation 32%), Verification (ˇ = −.47, p = .016, F2,24 = 4.58, p = .021, explanation of variation 22%), Stroop congruence (ˇ = −.46, p = .024, F2,24 = 2.92, p = .073, explanation of variation 13%), Stroop incongruence (ˇ = −.45, p = .026 F2,24 = 3.19, p = .059, explanation of variation 14%), Bourdon–Wiersma (ˇ = .49, p = .008 F2,24 = 7.36, p = .003, explanation of variation 33%), counting backwards (ˇ = .57, p = .004 F2,24 = 5.53, p = .011, explanation of variation 26%). Taken together the two analyses (Pearson correlation coefficients and multivariate regression analyses) the results in postmenopausal women changed in 7/62 variables.

The mean age at menopause in postmenopausal women was 50.1 years (SD 3.2) and the mean duration since menopause was 13.3 years (SD 4.8). The age at menopause did not correlate with cognitive performance. There was a trend of association with the duration since menopause in two variables in SRT (ˇ = −.61, p = .057, F3,20 = 1.91, p = .160, explanation of variation 11%) and in Stroop incongruence (ˇ = −.52, p = .077 F3,20 = 3.22, p = .045, explanation of variation 23%) so that longer duration associated with better performance. 4. Discussion Overall, cognitive performance was well preserved into late postmenopause. Perimenopausal women performed better than postmenopausal women in tests of visuomotor functions, visual episodic memory, and attention, whereas in verbal functions and in verbal episodic memory no differences were detected. When the effects of age and education were evaluated, the duration of education seemed to explain most of the variation in cognitive

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performance in postmenopausal women. The effect of age was the most apparent in visual episodic memory in postmenopausal, but also in verbal episodic memory, visuomotor functions and in some attentional tasks. In perimenopausal women the age affect was observed mostly in verbal episodic memory. Serum E2 level explained the cognitive performance of premenopausal women only in visual episodic memory and surprisingly, higher level of E2 associated with poorer performance. In linear regression analyses the results remained essentially the same. In postmenopausal women the age at menopause did not associate and the duration since menopause had only some random trend to correlate to cognitive performance with better performance in those with longer time since menopause. According to previous reports, age-related cognitive decline is especially evident in measures of processing speed [13], working memory [35], and learning ability [36]. Although in healthy ageing, substantial changes in cognition do not occur until the age of seventy, declining trends in such cognitive domains as visual memory are shown to appear earlier in late middle age [12,37]. All cognitive functions are not affected in a similar manner during ageing. For example, in a 16-year follow-up study by Zelinski and Burnight [38], the ability to recall visual material begun to decline already after the age of 55, whereas recognition memory remained unaffected even among 80–90 years old. Verbal abilities, such as reasoning and vocabulary, are also considered to be rather well-preserved during ageing [39] and that supports the findings from the present study where postmenopausal women, who were on average 16 years older than their perimenopausal controls, performed similarly both in tasks measuring verbal functions and verbal episodic memory. In this study, the association between longer education and better test performance was found only in postmenopausal women. This was true especially in tests of verbal functions and verbal episodic memory. In addition, longer education was associated with better performance in attention as well as in one of the tests measuring visuomotor abilities. Education could accordingly offer a protection against cognitive decline observed even in healthy ageing. Our findings in women around the menopausal transition were in line with earlier studies where longer education was related to better performance in tests measuring several verbal abilities [21] and visuomotor functions [40]. However, the study like ours could not evaluate the causality and thus not exclude the third mechanism, like intelligence quotient, affecting to both cognitive performance and level of education. Education may compensate the age-related cognitive decline [41], although others have not confirmed this connection [42]. Furthermore, higher education has been proposed to protect against mild cognitive impairment [22] and neurodegenerative diseases, such as Alzheimer’s disease [43]. According to the reserve hypothesis, education might provide a buffer, which postpones cognitive decline. A high level of education, cognitively demanding occupation, and stimulating environment add cognitive capacity and therefore provide alternative ways to compensate cognitive decline and even dementia [24]. Several studies support the hypothesis that individuals with more education are afforded greater protection from clinical manifestations caused by e.g. cortical atrophy [44]. In this study, the only association between E2 and cognitive performance was observed in visual episodic memory. Furthermore, the association was in the opposite direction than anticipated: higher E2 level was related to poorer performance. Sex hormones have been suggested to play an important regulatory role in neuropsychological functions [5]. Thus it has been proposed that substantial decrease of female sex hormones in the menopausal transition emphasize the natural age-related decline in cognitive performance. This presumption has been supported in surgically menopausal women, in whom a sudden drop in oestrogen has been

reported to lead to a decline in cognitive function [45]. However, in studies with naturally menopausal women, this kind of connection has not been verified [46]. The literature provides both pro and con (for review, see [47]) evidence that restoring hormone levels with HT after menopause improve cognitive performance. Taken together, the importance of endogenous and exogenous female sex hormones for cognition in general remains an open question, but the effect in menopausal transition seems to be marginal. The present study may be biased because of the subject selection process. Women were recruited via newspaper advertisements. This may have led women with concerns about their health or cognition to volunteer for the study. However, careful screening before the study reduced the possibility of such a bias source. We put effort to control confounding factors by excluding subjects with previous diseases, as well as smokers or users of central nervous system medicaments and alcohol. Conducting all tests at the same time of the day in the same quiet room validated that test performances between women were comparable. All perimenopausal women were tested in the same menstrual phase. Although the group sizes in this study were rather small, significant differences were observed. 4.1. Conclusion In conclusion, this study provides an important clinical implication: menopause, a natural event in women’s life span, is not inevitably an epochal hallmark for cognitive decline, but cognitive performance is quite well preserved still in late postmenopause. Although differences are found in performance between middleaged perimenopausal and late postmenopausal women, they seem to be more dependent on factors other than hormonal milieu, for instance of age or education. Education in particular may offer some protection against age-related cognitive decline. Contributors Hanna Tuomisto is the principal investigator and writer of the paper. Paula Salo is the co-investigator of the study and co-writer. Reetta Saarinen and Nea Kalleinen are the co-investigators of the study and Päivi Polo-Kantola is the leader of the study group, coinvestigator and co-writer. Competing interests All authors have no conflicts of interest pertaining to this manuscript. Additionally, all authors declare that they have contributed substantially to this manuscript. Funding This study has not been founded. Ethical approval The study had approval from the Ethics Committee of Turku University Central Hospital. References [1] Greendale GA, Wight RG, Huang MH, et al. Menopause-associated symptoms and cognitive performance: results from the study of women’s health across the nation. Am J Epidemiol 2010;171(11):1214–24. [2] Sullivan Mitchell E, Fugate Woods N. Midlife women’s attributions about perceived memory changes: observations from the Seattle Midlife Women’s Health Study. J Womens Health Gend Based Med 2001;10(4):351–62. [3] Greendale GA, Huang MH, Wight RG, et al. Effects of the menopause transition and hormone use on cognitive performance in midlife women. Neurology 2009;72(21):1850–7.

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