This article was downloaded by: [Ulster University Library] On: 03 April 2015, At: 03:51 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

Aging, Neuropsychology, and Cognition: A Journal on Normal and Dysfunctional Development Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/nanc20

Sex differences in cognitive training effects of patients with amnestic mild cognitive impairment a

a

a

ab

Julia Rahe , Jennifer Liesk , Jan B. Rosen , Annette Petrelli , bc

bc

b

Stephanie Kaesberg , Oezguer A. Onur , Josef Kessler , Gereon R. Fink

bc

ab

& Elke Kalbe

a

Click for updates

Institute of Gerontology & Center for Neuropsychological Diagnostics and Intervention (CeNDI), University of Vechta, Vechta, Germany b

Department of Neurology, University Hospital Cologne, Cologne, Germany c

Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, Jülich, Germany Published online: 30 Mar 2015.

To cite this article: Julia Rahe, Jennifer Liesk, Jan B. Rosen, Annette Petrelli, Stephanie Kaesberg, Oezguer A. Onur, Josef Kessler, Gereon R. Fink & Elke Kalbe (2015): Sex differences in cognitive training effects of patients with amnestic mild cognitive impairment, Aging, Neuropsychology, and Cognition: A Journal on Normal and Dysfunctional Development, DOI: 10.1080/13825585.2015.1028883 To link to this article: http://dx.doi.org/10.1080/13825585.2015.1028883

PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims,

proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content.

Downloaded by [Ulster University Library] at 03:51 03 April 2015

This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://www.tandfonline.com/page/termsand-conditions

Aging, Neuropsychology, and Cognition, 2015 http://dx.doi.org/10.1080/13825585.2015.1028883

Sex differences in cognitive training effects of patients with amnestic mild cognitive impairment Julia Rahea, Jennifer Lieska, Jan B. Rosena, Annette Petrellia,b, Stephanie Kaesbergb,c, Oezguer A. Onurb,c, Josef Kesslerb, Gereon R. Finkb,c and Elke Kalbea,b*

Downloaded by [Ulster University Library] at 03:51 03 April 2015

a

Institute of Gerontology & Center for Neuropsychological Diagnostics and Intervention (CeNDI), University of Vechta, Vechta, Germany; bDepartment of Neurology, University Hospital Cologne, Cologne, Germany; cCognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, Jülich, Germany (Received 24 June 2014; accepted 5 March 2015) Cognitive training has been shown to be effective in improving cognitive functions in patients with Mild Cognitive Impairment (MCI). However, data on factors that may influence training gains including sociodemographic variables such as sex or age is rare. In this study, the impact of sex on cognitive training effects was examined in N = 32 age- and education-matched female (n = 16) and male (n = 16) amnestic MCI patients (total sample: age M = 74.97, SD = 5.21; education M = 13.50, SD = 3.11). Patients participated in a six-week multidomain cognitive training program including 12 sessions each 90 min twice weekly in mixed groups with both women and men. Various cognitive domains were assessed before and after the intervention. Despite comparable baseline performance in women and men, we found significant interaction effects Time × Sex in immediate (p = .04) and delayed verbal episodic memory (p= .045) as well as in working memory (p = .042) favoring the female MCI patients. In contrast, the overall analyses with the total sample did not reveal any significant within-subject effects Time. In conclusion, our results give preliminary evidence for stronger cognitive training improvements of female compared to male MCI patients. More generally, they emphasize the importance of sex-sensitive evaluations of cognitive training effects. Possible underlying mechanisms of the found sex differences are discussed and directions for future research are given. Keywords: mild cognitive impairment; cognitive training effects; cognitive plasticity; sex difference; prevention of dementia

Mild Cognitive Impairment (MCI) is characterized by subjective complaints of cognitive deficits and objectively impaired cognitive functions, while activities of daily living are largely unimpaired (Petersen, 2011; Petersen et al., 2001). As the prevalence of MCI is high with 10–20% in persons aged over 65 years (Petersen, 2011), and as MCI in many cases also constitutes a prodromal state of dementia (with conversion rates of 5–15% per year (Mitchell & Shiri-Feshki, 2009; Petersen, 2004) and long-term conversion rates of up to 80% (Petersen et al., 2001), efficient intervention strategies are of utmost importance. The etiology of MCI has been reported to be multifactorial with several protective (e.g., cognitively stimulating activity, physical activity, or Mediterranean diet) and risk factors (e.g., smoking or heavy alcohol consumption) mediating or moderating brain *Corresponding author. Email: [email protected]; [email protected] Julia Rahe and Jennifer Liesk contributed in equal parts to this manuscript and therefore share the first authorship. © 2015 Taylor & Francis

Downloaded by [Ulster University Library] at 03:51 03 April 2015

2

J. Rahe et al.

function in the preclinical stage and the further course of the disease (Huckans et al., 2013). Therefore, it has been stated that neuronal and cognitive plasticity are maintained even in MCI patients (Huckans et al., 2013; Simon, Yokomizo, & Bottino, 2012), thereby opening a window for possible intervention. In terms of secondary prevention, targeting these factors to induce plasticity might help delay or even prevent the conversion to dementia. Moreover, the current lack of pharmacological treatment of MCI (Cooper, Li, Lyketsos, & Livingston, 2013; Li et al., 2011; Petersen, 2011; Simon et al., 2012) further supports the investigation of nonpharmacological interventions. In this context, it has been concluded that cognitive training has the potential to enhance global cognitive function in MCI patients at least in the short term (Gates, Sachdev, Fiatarone Singh, & Valenzuela, 2011; Jean, Bergeron, Thivierge, & Simard, 2010; Li et al., 2011; Simon et al., 2012; Teixeira et al., 2012). Most consistently, specific effects on cognitive domains targeted in cognitive training programs have been reported rather than generalized effects (Reijnders, Van Heugten, & Van Boxtel, 2013; Simon et al., 2012). Here, improvements in the domains of memory, executive functioning, working memory, visuospatial ability, attention, or processing speed have been described (Huckans et al., 2013; Li et al., 2011). Importantly, these cognitive gains induced by cognitive training have been interpreted as retained cognitive reserve of MCI patients (Simon et al., 2012) and cognitive training could be a possible strategy to further increase cognitive reserve in MCI patients (Huckans et al., 2013; Teixeira et al., 2012). Despite the positive results of many intervention studies, Martin, Clare, Altgassen, Cameron, and Zehnder (2011) concluded in their review that data is inconclusive yet. On the one hand, cognitive interventions in MCI patients appear to be effective, but gains were partly comparable to those of active control groups such as physical training and drug treatment alone or in combination with strategy training, questioning the specificity of cognitive training effects. On the other hand, inconsistencies concerning improved domains after cognitive training in MCI patients exist. These can partially be explained by different definitions of cognitive training, lack of power, heterogeneity of MCI patients, or variability in methodological quality and statistical analyses (Cooper et al., 2013; Gates et al., 2011; Huckans et al., 2013; Jean et al., 2010; Li et al., 2011; Martin et al., 2011; Teixeira et al., 2012). Furthermore, some of the discrepancies might be explainable by the influence of other factors on the response to cognitive training. For example, first evidence exists that for MCI patients and patients suffering from mild to moderate dementia, biological factors such as lower cholesterol and higher levels of brain-derived neurotropic factor at baseline (MCI; Suzuki et al., 2013) or carrying apoE-4 (MCI and dementia; Binetti et al., 2013) have been identified to be predictive for better outcome in cognitive functions. Furthermore, sociodemographic factors such as higher age at baseline (dementia; Aguirre et al., 2013), low education (MCI and dementia; Olazaran et al., 2004), or female sex (dementia; Aguirre et al., 2013) have been discussed to predict higher training gains, but data is too rare to draw clear conclusions yet. Referring to sex differences, a large body of literature exists, indicating different profiles of strengths and weaknesses in cognitive functions. For example, many studies strengthened the hypothesis of women’s advantage in verbal and episodic memory tasks with a focus on verbal processing, whereas men seem to perform on a higher level in tasks with focus on visuospatial abilities – especially mental rotation – and visuospatial episodic memory tasks (Beinhoff, Tumani, Brettschneider, Bittner, & Riepe, 2008; De Frias, Nilsson, & Herlitz, 2006; Duff, Schoenberg, Mold, Scott, & Adams, 2011; Herlitz, Nilsson, & Bäckman, 1997; Herlitz & Yonker, 2002; Lewin, Wolgers, & Herlitz, 2001; Masters & Sanders, 1993; Munro et al., 2012; Proust-Lima et al., 2008; Wiederholt et al.,

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Aging, Neuropsychology, and Cognition

3

1993). These profiles have been reported to be stable in subjects aged 35–80 years over a period of 10 years (De Frias et al., 2006) and seem to be comparable between young and older adults (Munro et al., 2012). In MCI patients especially immediate and delayed verbal episodic memory tasks appear to be sensitive for sex differences. Although data is rare, it seems that the pattern matches those of healthy older adults, because females showed significantly higher performance in verbal episodic memory than males in a study by Beinhoff et al. (2008). Furthermore, although the male advantage in visuospatial abilities was only evident on a descriptive level (failing significance), the authors concluded that the advantage in sex-specific cognitive domains of healthy older adults might result in larger plasticity, particularly in verbal episodic memory (female) versus visuospatial abilities (male). Beinhoff et al. (2008) summarized these sex-specific differences in a model of “gender-specific cognitive reserve,” which could also be conceptualized as sex-specific plasticity. Taking together (i) the fact that sex differences exist in cognitive profiles of healthy women and men as well as female and male MCI patients, (ii) the notion of sex-specific plasticity in MCI patients (cf. Beinhoff et al., 2008), and (iii) preliminary evidence that sex influences cognitive training effects in patients with Alzheimer´s disease, the question arises whether sex has an impact on the effects of cognitive training in MCI patients. Evidence of sex effects on cognitive training improvements would have important implications for evaluation of cognitive training as well as development of interventions with regard to specific female and male resources. Thus far, these aspects have been widely neglected. Regarding this point, Baron, Ulstein, and Werheid (2015) analyzed the reporting of gender distribution and gender differences in 73 randomized controlled trials evaluating the effects of psychosocial interventions in persons with Alzheimer’s disease and amnestic MCI. In conclusion, solely 62% of the included studies describe the gender ratios and only 19% report the analysis of gender effects. Thus, the aim of this study was to evaluate possible differences in the cognitive gains of female and male amnestic MCI patients after cognitive training. Based on the literature and arguments outlined above, and especially the model of sex-specific cognitive plasticity proposed by Beinhoff et al. (2008), we hypothesized that sex differences in improvements after cognitive training in patients with amnestic MCI patients exist. In more detail, we expected different gains in those domains that have been described to be sex-sensitive with women benefitting more in verbal episodic memory and men showing more gains in visuospatial abilities. Furthermore, as a more exploratory question, the possible influence of sex on other cognitive domains as well as overall cognitive performance was evaluated.

Methods Study population and procedure Data of n = 38 amnestic MCI patients (n = 22 women; n = 16 men) were reanalyzed. We selected data from an existing database of participants who were recruited and trained with cognitive training at the Memory Clinic of the University Hospital Cologne, Germany, from 2007 to 2010. As more women were listed in the database (n = 22) and as an equal sample size was aimed at, we used the data sets of all men (n = 16) and then selected an equal number of women (n = 16) matched for age and education. Amnestic MCI was diagnosed in all cases on the basis of medical history and neuropsychological testing. According to the criteria of Petersen et al. (2001) we operationalized amnestic MCI as (i) performance below 1.5 SD of age-corrected normative

Downloaded by [Ulster University Library] at 03:51 03 April 2015

4

J. Rahe et al.

data in the Memo Test (Schaaf, Kessler, Grond, & Fink, 1992) or the DemTect subtests immediate or delayed recall (Kalbe et al., 2004), (ii) report of subjective memory complaints in the medical history, and (iii) no impairment in activities of daily living according to medical history. The DemTect has been proven to have high sensitivity of over 80% to detect MCI (Kalbe et al., 2004; Scheurich et al., 2005). The Memo Test (Schaaf et al., 1992) is a classical word list learning task with 10 words and an immediate selective reminding condition in five trials as well as a delayed recall condition and thus uses a well-established task paradigm in the diagnosis of MCI (Modrego, 2006; Petersen, 2004). Next to existence of amnestic MCI, further inclusion criteria were age 50–100 years, normal or corrected-to-normal vision and hearing, and German as native language. Patients were excluded in case of life-threatening illness, history of another neurological or psychiatric disease (past or present), alcohol or drug abuse, and clinically relevant symptoms of depression at pretest as assessed with the German Beck Depression Inventory 2 (BDI 2; ≥20 points; Hautzinger, Keller, & Kühner, 2009). Furthermore, participants were excluded posthoc from analysis if they participated in less than 8 of 12 cognitive training sessions. The study was endorsed by the Ethics Committee of the University Hospital Cologne and each patient gave informed written consent.

Intervention The standardized neuropsychological program NEUROvitalis (Baller, Kalbe, Kaesberg, & Kessler, 2009) was used as cognitive training in groups with a maximum of eight participants. Groups were mixed with female and male participants. NEUROvitalis targets the age-sensitive domains attention, memory, and executive functions. It can be applied with two degrees of difficulty, which enables the adaption to the performance level of participants. In this study the easier level was used as MCI patients already show detriments in some of the targeted domains. The cognitive training consisted of 12 90min sessions and was administered twice weekly over a period of six weeks. Each session was completely structured and participants performed group games, single and group tasks in the form of paper-pencil tasks, verbal exercises, or board games. Participants were also asked to perform cognitive homework for 10 min each day. Furthermore, patients received cognitive homework for the time between the sessions and were advised to train at least for 10 min each day. Intensity of the homework was not controlled for beyond these aspects. However, as homework was discussed at the beginning of each training session the motivation to do them was very high. Sessions were conducted by certified trainers with experience in neuropsychological training with older adults.

Neuropsychological assessment Before and after the training all patients completed a standardized neuropsychological test battery to assess overall cognitive performance as well as performance in the domains of memory, executive functions, visuo-construction, and number transcoding. Furthermore, the German BDI 2 (Hautzinger et al., 2009) was used at pretest to screen participants for depressive symptoms. The neuropsychological assessment lasted approximately two hours and was conducted by research assistants trained in neuropsychological testing and scoring. When available, parallel forms were used to counteract retest effects.

Aging, Neuropsychology, and Cognition

5

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Overall cognitive performance The screening instruments Mini Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1975) and DemTect (Kalbe et al., 2004) were used for the assessment of overall cognitive performance. The MMSE is a short screening instrument consisting of 30 items of temporal and local orientation, short-term memory, attention, visuo-construction, and language. The DemTect is a screening instrument for the detection of MCI and mild dementia, which is independent of sociodemographic factors and available in a parallel form. It is divided in five subtasks to evaluate immediate and delayed verbal memory (word list immediate and delayed recall), number processing (number transcoding), and executive functions (supermarket [version A]/animals [parallel version B], digit span backwards). The age-corrected total DemTect score was used as an indicator for overall cognitive performance and parallel versions for pretest and posttest were used (Kessler, Calabrese, & Kalbe, 2010).

Memory Immediate and delayed verbal memory as well as figural memory were assessed with several (sub-)tests.

Verbal episodic memory As a measure of episodic immediate and delayed verbal memory the Memo Test (Schaaf et al., 1992) was performed. It consists of five trials. At the beginning, experimenters read out 10 words that participants had to reproduce immediately. In the following four trials, exclusively the forgotten words (of the preceding trial) were repeated, but participants had to reproduce all 10 words. Delayed recall was prompted 15 min later. As another measure of verbal episodic memory, the DemTect (Kalbe et al., 2004) subtests immediate and delayed recall of the 10-word list were used. Assessors read out a 10-word list that participants had to reproduce immediately. Afterwards, the whole list was repeated and the participants had to reproduce as many words as possible again. Delayed recall of the word list was prompted 10 min later. The total numbers of correctly reproduced words in each trial were used for analysis. Parallel forms were used for both Memo Test and DemTect.

Figural memory The delayed recall of the Complex Figure Test (CFT; Lezak, Howieson, & Loring, 2004) was performed to assess figural memory. Participants copied the complex figure (as described in section visuo-construction) and had to draw it again 30 min later from memory. Elements were evaluated concerning correctness of position and shape and a total score was used for analyses. The Rey Complex Figure and the Modified Taylor Figure were used as parallel forms (Lezak et al., 2004).

Executive functions Five tasks were administered to assess working memory, verbal fluency, and executive control.

6

J. Rahe et al.

Working memory In the DemTect subtest digit span backwards (Kalbe et al., 2004) participants had to repeat orally digit spans of two to six numbers in reverse order. For each item, maximum two trials were given and the sum of numbers in the longest correctly repeated digit span was used for data analysis.

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Verbal fluency The DemTect subtest supermarket (version A)/animals (parallel version B; Kalbe et al., 2004) was used as a measure of semantic verbal fluency. The task was to generate as many words of the semantic category as possible within one minute. The age-corrected score of the correctly named items was used for analysis. As a measure of letter verbal fluency, the Controlled Oral Word Association Test (COWA; Spreen & Strauss, 2006) was used. The task was to generate as many words as possible within one minute, beginning with a specific letter (F, A, or S). The sum of words generated for all three letters was used for analysis.

Executive control The Trail Making Tests A and B (TMT-A, -B; Reitan & Wolfson, 1993) were used to assess speed of processing, respectively, set shifting. In TMT-A participants had to connect numbers from 1 to 25, as fast as possible. In TMT-B participants had to connect alternately Arabic numbers (1–13) and letters (A–L). Time was assessed for both tasks. The difference of seconds required for part B minus seconds required for part A (TMT BA) was analyzed as a purer measure of executive control (cf. Corrigan & Hinkeldey, 1987).

Visuo-construction Visuo-constructive ability was tested with the CFT (Lezak et al., 2004). Participants had to copy a figure consisting of 18 single elements. For scoring, correctness of position and shape was evaluated. Parallel forms were used for retest.

Number processing The number transcoding subtest of the DemTect (Kalbe et al., 2004) was used to assess participants’ number-processing abilities. Participants were asked to transfer two Arabic numbers into numeral words and – conversely – two numeral words into Arabic numbers. The correctly transformed items were scored with one point each and the sum was used for data analysis.

Statistical analyses Statistical analyses were performed using IBM SPSS Statistics 21 for Windows (2013). Baseline differences in demographics and cognitive performance between female and male MCI patients were compared with t-tests for independent samples (age, DemTect, Memo, and MMST scores) and a Mann–Whitney test (education) with a significance level of α = .05.

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Aging, Neuropsychology, and Cognition

7

We analyzed the cognitive training gains from pretest to posttest using ANOVAs for repeated measures (rANOVAs) with a significance level of α = .05. The within-subject variable Time (pretest to posttest) and the between-subject variable Sex (female vs. male) both had two levels. The covariates age and education were included in the rANOVAs as both have been described as potential confounders of sex differences (Gerstorf, Herlitz, & Smith, 2006; Kramer, Yaffe, Lengenfelder, & Delis, 2003; Lamar, Resnick, & Zonderman, 2003; Le Carret et al., 2005; Moreno-Martínez, Laws, & Schulz, 2008; Wahlin, MacDonald, Defrias, Nilsson, & Dixon, 2006). Even though the male and female subsamples of the present study were matched for these variables, the matching was not perfect. Therefore, we used the most conservative approach to analyze our data by controlling for further bias with age and education as covariates. We used the interaction Time × Sex as an indicator for sex differences in the training gains. The effect size partial η2 (ηp2) was estimated for overall effects of the rANOVAs (small: ηp2 > 0.01; moderate: ηp2 > 0.06; strong: ηp2 > 0.14; Bühner & Ziegler, 2009). As a posthoc test of the significant overall effects of the rANOVAs, we calculated pairwise comparisons for further analyses. The Sidak correction was used to prevent an inflated type I error of multiple comparisons, with an overall α = .05 and the effect size d was estimated indicating a small (d > 0.10), moderate (d > 0.30), or strong effect (d > 0.50; Field, 2009).

Results As described in the Methods section, we analyzed the data of N = 32 amnestic MCI patients: n = 16 men and n = 16 age- and education-matched women. Owing to the study design no dropout rate exists. Table 1 shows the demographics of the study sample at baseline as well as depressive symptoms, overall cognitive functioning, and memory performance. At pretest, female and male MCI patients did not differ significantly in age, education, depressive symptoms, overall cognitive performance, or memory performance (all p > .05, see Table 1). Cognitive performance of female and male MCI patients and the total sample at pretest and posttest is summarized in Table 2. We did not find significant differences between women and men in any cognitive domain at baseline. Analyzing possible sex differences in training gains of women and men, the rANOVAs revealed significant Time × Sex interactions in favor of the female MCI patients for immediate verbal memory (Memo-Test, immediate recall; cf. Figure 1), F (1, 28) = 4.58, MSE = 0.55, p = .04, ηp2 = 0.14, delayed verbal memory (Memo-Test, delayed recall, cf. Figure 2), F (1, 28) = 4.46, MSE = 0.83, p = .04, ηp2 = 0.14, and working memory (DemTect, digit span backwards, cf. Figure 3), F (1, 28) = 4.47, MSE = 0.37, p = .04, ηp2 = 0.14. In addition, a nonsignificant trend for a Time × Sex interaction was found in letter verbal fluency (COWA), F (1, 28) = 2.99, MSE = 37.67, p = .10, ηp2 = 0.10, in favor of the female MCI patients as well. Furthermore, we found a trend for a between-subject effect Sex in overall cognitive performance (MMST), F (1, 28) = 2.76, MSE = 1.79, p = .11, ηp2 = 0.09. Posthoc pairwise comparisons for overall cognitive performance revealed that the female MCI patients were slightly better than the male at posttest, but this effect only showed a statistical trend (MMST), meandiff (females – males) = 1.13, p = .11, d = 0.66, 95% CI (−0.29–2.56). No significant interaction effects Time × Sex were found for the other cognitive domains.

(5.14) (3.07) (8.28)

(1.60) (1.39)

(2.48) (1.47) (1.11) (2.10)

74.51 12.69 8.18

27.13 12.25

11.56 1.81 5.35 2.29

(SD)

7.00–16.00 0.00–4.00 2.40–7.00 0.00–7.00

23–30 9–15

66–86 8–18 0–19

Range

10.69 1.06 5.35 2.25

26.50 11.50

75.13 14.31 8.56

M

(1.96) (1.18) (1.23) (1.88)

(1.71) (2.00)

(5.44) (3.03) (4.93)

(SD)

♂ (n = 16)

8.00–15.00 0.00–3.00 4.00–9.40 0.00–6.00

23–29 9–15

67–85 10–18 2–18

Range

M 74.97 13.50 8.38 26.81 11.88 11.13 1.44 5.35 2.22

p .87b .13c .88b .48b .23b .28b .12b .99b .93b

(2.24) (1.37) (1.15) (1.96)

(1.66) (1.74)

(5.21) (3.11) (6.70)

(SD)

7.00–16.00 0.00–4.00 2.40–9.40 0.00–7.00

23–30 9–15

66–86 8–18 0–19

Range

Total sample (N = 32)

Notes: IM = immediate; D = delayed. a The Beck Depression Inventory 2 was used as an indicator for depressive symptoms; bcomparison of groups at baseline with t-tests for independent samples; ccomparison of groups at baseline with Mann–Whitney tests.

Age Education Depressive symptomsa Cognitive status MMST DemTect Memory DemTect, IM DemTect, D Memo, IM Memo, D

M

♀ (n = 16)

Baseline demographics of the study sample.

Demographics

Table 1.

Downloaded by [Ulster University Library] at 03:51 03 April 2015

8 J. Rahe et al.

5.35 2.19 11.56 1.81 10.53 4.63 111.44 3.38 31.69 33.31 3.38

10 10 20 10

36

6

-

4 –

36

4

(0.72)

(2.65)

(0.96) (11.76)

(65.77)

(1.09)

(5.80)

(1.11) (2.10) (2.48) (1.47)

(1.60) (1.39)

3.69

33.68

3.38 35.93

85.13

5.13

12.25

6.41 3.75 12.37 2.94

28.27 13.94

(0.48)

(4.29)

(0.96) (10.86)

(50.94)

(0.89)

(6.86)

(1.25) (2.44) (2.83) (2.26)

(1.16) (2.89)

Posttest

3.25

32.44

3.25 33.63

86.67

4.69

11.16

5.35 2.25 10.69 1.06

26.50 11.50

(0.86)

(3.88)

(1.00) (10.58)

(44.77)

(0.95)

(7.71)

(1.23) (1.88) (1.96) (1.18)

(1.71) (2.00)

Pretest

3.56

33.19

3.75 32.56

68.20

4.37

12.84

5.51 2.81 11.56 1.56

(0.73)

(3.23)

(0.68) (11.89)

(34.14)

(1.09)

(7.49)

(1.00) (2.07) (1.75) (1.50)

(2.32) (1.78)

Posttest 27.06 12.69

M (SD)

M (SD)

3.31

32.88

3.31 32.66

99.45

4.66

10.84

5.35 2.22 11.13 1.44

26.81 11.88

(0.78)

(3.30)

(0.97) (11.04)

(57.06)

(1.00)

(6.72)

(1.15) (1.96) (2.24) (1.37)

(1.66) (1.74)

Pretest

3.63

33.43

3.56 34.25

76.94

4.75

12.55

5.96 3.28 11.97 2.25

(0.61)

(3.74)

(0.84) (11.33)

(43.76)

(1.05)

(7.07)

(1.20) (2.28) (2.35) (2.02)

(1.92) (2.44)

Posttest 27.65 13.31

M (SD)

Total sample (N = 32)

Notes: Max. = maximum; DR = subtest delayed recall; DSB = subtest digit span backwards; IR = subtest immediate recall; NT = subtest number transcoding; S/A = subtest supermarket/animal; TMT B-A = difference of part B minus by part A. a Parallel versions were used to minimize retest effects; bage-corrected transcoded subscores were used; cdue to error in measurement of TMT-B the data of n = 1 male had to be excluded from the analysis.

27.13 12.25

Pretest

30 18

Max. score

♂ (n = 16)

♀ (n = 16)

Cognitive performance of Female and Male amnestic MCI patients and the total sample at pretest and posttest.

Cognitive status MMST DemTectb Memory Verbal memory Memo Test, IRa Memo Test, DRa DemTect, IRa DemTect, DRa Figural memory CFT, DRa Executive functions Working memory DemTect, DSBa Executive control TMT B-Ac Verbal fluency Semantic: DemTect, S/Aa,b Letter: COWA Visuo-construction CFT, Copya Number processing DemTect, NT a

Domain

Table 2.

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Aging, Neuropsychology, and Cognition 9

Downloaded by [Ulster University Library] at 03:51 03 April 2015

10

J. Rahe et al.

Figure 1. Means in Memo Test, subtest immediate recall (Schaaf et al., 1992) representing changes in immediate verbal memory from pretest to posttest. A significant interaction effect Time × Sex (F = 4.58, p = .04, ηp2 = 0.14) was found in favor of the female MCI patients.

Figure 2. Means in Memo Test, subtest delayed recall (Schaaf et al., 1992) representing changes in delayed verbal memory from pretest to posttest. A significant interaction effect Time × Sex (F = 4.46, p = .04, ηp2 = 0.14) was found in favor of the female MCI patients.

Remarkably, we did not find any significant changes for the overall within-subjects effects Time in either of the measured cognitive domains when sex was not included in the interaction term (all p > 0.05).

Discussion The aim of this study was to evaluate sex differences in the cognitive gains of amnestic MCI patients after a multidomain cognitive training intervention. Our main findings are that in our sample of age- and education-matched amnestic MCI patients with comparable baseline performance, women showed stronger improvements in immediate and delayed verbal episodic memory as well as in working memory after a six-week cognitive training as demonstrated by significant interaction effects Time × Sex. Nonsignificant trends

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Aging, Neuropsychology, and Cognition

11

Figure 3. Means in DemTect, subtest digit span backwards (Kalbe et al., 2004) representing changes in working memory from pretest to posttest. A significant interaction effect Time × Sex (F = 4.47, p = .04, ηp2 = 0.14) was found in favor of the female MCI patients.

additionally support these findings. Compared to men, women showed stronger gains in letter verbal fluency from pretest to posttest and even outperformed men in overall cognitive performance after the training. Importantly, the overall analyses with the total sample (within-subject effect Time) and without comparing women and men (interaction effect Time × Sex) did not reveal any significant effect on the cognitive domains. In sum, our results support our hypothesis that sex differences in the cognitive training effects of amnestic MCI patients can be found in verbal memory with females benefitting stronger. They do not support the hypotheses that men improve stronger in visuospatial abilities. In addition, we found women to show stronger benefits in working memory and letter verbal fluency, two domains that are supposed to be related with each other and with verbal episodic memory (e.g., Cabeza, Dolcos, Graham, & Nyberg, 2002; Daneman, 1991). Several studies have shown the potential of cognitive training to enhance episodic and working memory functions in MCI patients (cf. Belleville et al., 2006; Günther, Schäfer, Holzner, & Kemmler, 2003; Huckans et al., 2013; Li et al., 2011), but did not address sex differences. However, in our study only the female MCI patients showed benefits in these domains after participation in cognitive training. Importantly, when sex was not included in the overall analyses we could not find significant improvements in any cognitive domain as the stronger cognitive effects of the female patients were masked by the lessstrong cognitive gains of the male patients. This finding is striking, because it underlines the possibility that the lack of significant improvements after cognitive training in some studies with MCI patients might be biased by the negligence of sex-specific gains. Therefore, it seems reasonable that the heterogeneous results of cognitive training studies in MCI patients might not solely be attributable to inconsistencies in definitions of cognitive training, lack of power, or heterogeneity of MCI patients (Cooper et al., 2013; Gates et al., 2011; Huckans et al., 2013; Jean et al., 2010; Li et al., 2011; Martin et al., 2011; Teixeira et al., 2012). Based on the results of our study and in line with the conclusion of Baron et al. (2015), we suppose that also sex differences need to be focused when evaluating cognitive training effects in amnestic MCI patients. Our findings are in line with few studies that found sex differences in the effects of neuropsychological interventions in patients suffering from dementia favoring female patients. Kurz et al. (2012) found significantly more pronounced benefits on depressive

Downloaded by [Ulster University Library] at 03:51 03 April 2015

12

J. Rahe et al.

symptoms (but not cognitive functions) after a neuropsychological training in female patients suffering from early dementia. Moreover, in a recent study of cognitive training in dementia patients, Aguirre et al. (2013) reported that female sex was predictive for increased gains in the overall cognitive performance score of the ADAS-Cog (Rosen, Mohs, & Davis, 1984). In line with studies that strengthen the argument of a general female advantage in verbal episodic memory tasks (Beinhoff et al., 2008; De Frias et al., 2006; Duff et al., 2011; Herlitz et al., 1997; Herlitz & Yonker, 2002; Lewin et al., 2001; Masters & Sanders, 1993; Munro et al., 2012; Proust-Lima et al., 2008; Wiederholt et al., 1993), we found improvements of female amnestic MCI patients especially in the putative sex-sensitive domains of verbal episodic memory. We interpret these findings in line with the model of “sex-specific cognitive reserve” proposed by Beinhoff et al. (2008) and therefore assume that female amnestic MCI patients might be more capable of activating their former resources in verbal domains. Following this notion, we suppose that the female participants in our study benefitted from their former greater cognitive plasticity in verbal episodic and working memory. However, for the men, our results are not consistent with our hypothesis. We expected men to show stronger effects in tasks of visuospatial abilities – the domain that is supposed to be especially strong in men – but could not support this assumption. This result is in line with the results of Beinhoff et al. (2008) who found no gender differences for encoding and retaining of visuospatial material as well. Thus, there is no evidence for a sex-specific cognitive plasticity advantage in visuospatial abilities for male MCI patients. However, this unexpected result could be caused by some other biasing factors. One explanation could be the type of cognitive training that was used in our study. The used NEUROvitalis program (Baller et al., 2009) favors domains in which women are typically superior as it mainly includes verbal material and exercises. Furthermore, most sessions focused on memory or mnemonic strategies for different situations of everyday life. The training also contains the activation game “city map” of the program that specifically trains visuospatial ability. However, this game was played in only three of twelve sessions. Thus, the focus on verbal memory might explain why neither women nor men showed significant improvements in visuospatial ability or figural memory. However, as a more general problem for the current topic of interest, it should be emphasized that most cognitive group interventions are composed of verbal material and the majority of neuropsychological assessments (e.g., those assessing episodic memory in MCI and dementia patients) use primarily verbal tasks as well. Thus, it is important that future investigations aiming at unraveling sex differences use trainings and neuropsychological tests that are well-balanced with regard to verbal and nonverbal material. There are a number of possible mechanisms discussed in the literature that may contribute to sex-specific cognitive plasticity. The results of some studies indicated that the age-related loss of gray matter begins earlier in men and that the total atrophic changes seem to be higher in men (Coffey et al., 1992; Gur et al., 1991; Pruessner, Collins, Pruessner, & Evans, 2001; Raz et al., 2004). According to Larrabee and Crook (1993) these sex differences in structural decline appear more pronounced in the left hemisphere, which is associated with verbal memory functions (Kramer et al., 2003) – a finding that is in line with our results. In addition, age-related progress in loss of white matter appears to be greater in men as well (Ropele et al., 2010). Furthermore, sex has been considered as an important influencing factor on brain connectivity (Gong, He, & Evans, 2011), although evidence is controversial and a clear direction towards sex-specific patterns of connectivity cannot be described so far (Fjell et al., 2009).

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Aging, Neuropsychology, and Cognition

13

The neuroprotective role of estrogen on verbal memory performance has been considered as well (Boss, Kang, Marcus, & Bergstrom, 2014; Eberling et al., 2003; Henderson, Watt, & Buckwalter, 1996; Kramer et al., 2003; Li & Singh, 2014). A study by Verghese et al. (2000) provides evidence that older women on estrogen replacement therapy performed significantly better on different verbal memory tests than control subjects. However, findings are controversial (Boss et al., 2014) and unfortunately information about estrogen replacement therapy was not assessed in our study so that the particular role of hormones in the reported training effects remains unclear. Furthermore, an influence of estrogen could explain a general superiority of women in verbal memory tests, but not stronger cognitive gains after cognitive training. To our knowledge, the notion whether estrogen replacement therapy might also been associated with higher cognitive plasticity has not been discussed thus far. Furthermore, sociodemographic factors such as education have been discussed to be related to sex-specific cognitive performance in cognitively impaired older subjects (Le Carret et al., 2005). Education has been associated with cognitive reserve (Stern, 2009) and lower formal education of women has been discussed as an important influencing factor for lower cognitive reserve of women (Van Exel et al., 2001). Beyond that, Olazaran et al. (2004) reported lower education to be predictive for cognitive training gains. These contradictory arguments do not allow a clear expectation whether elderly women (who typically have received less formal education in that generation) would profit more or less from cognitive training. In our study, the female amnestic MCI patients showed greater cognitive plasticity in verbal abilities than male patients and this finding was even independent of the educational background, because education was integrated as a covariate into the rANOVAs to exclude its influence on training effects. In addition, it has to be emphasized that women and men were matched for education at baseline so that the premise for the hypothesis of lower cognitive reserve in women as proposed by Van Exel et al. (2001) may be inapplicable for our study sample. Thus, although our data indicates even higher cognitive plasticity in women, this aspect will have to be examined more thoroughly in further studies. Importantly, the performance of our female and male amnestic MCI patients did not differ significantly in any cognitive domain at baseline. This was unexpected, as verbal episodic memory and visuospatial abilities are presumed to be sex-sensitive in healthy older adults (De Frias et al., 2006; Duff et al., 2011; Munro et al., 2012; Proust-Lima et al., 2008; Wiederholt et al., 1993) as well as MCI patients (Beinhoff et al., 2008). However, it seems reasonable that the matching of female and male patients for age and especially education could have resulted in the comparable baseline performance. A number of potential limitations needs to be considered when interpreting the findings of our study. First, our results have restricted generalizability because we did not perform a randomized controlled trial. Thus, it is unclear whether the training benefits found for women would remain significant when compared to effects of a control group. However, our aim was not to demonstrate cognitive training effects in MCI patients, which have been shown in other investigations (Gates et al., 2011; Jean et al., 2010; Li et al., 2011; Simon et al., 2012; Teixeira et al., 2012). Rather, the specific focus of our study was on putative sex-specific differences in the cognitive training gains and due to this an analysis of an age- and education-matched sample of female and male amnestic MCI patients seems appropriate. Second, the significant interaction effect for working memory occurs with an increase in performance of the women on the one hand and a greater variability of the men on the other. Therefore this effect seems not as clear as the found effects on verbal memory, and future studies will have to confirm our preliminary

Downloaded by [Ulster University Library] at 03:51 03 April 2015

14

J. Rahe et al.

findings. Third, research assistants conducting the neuropsychological tests were not blinded for the point of assessment (pretest or posttest). However, an influence of the research assistants on our findings is unlikely because the sex-specific analyses of data were unknown at the time of data collection so that the sex-specific training gains cannot be derived to experimenter’s expectation. Fourth, we did not formally assess individual motivation or effort of the participants during the training and in the pretest and posttest (just as in most comparable studies; e.g., Belleville et al., 2006; Binetti et al., 2013; Konsztowicz, Anton, Crane, Moafmashhadi, & Koski, 2013). Thus, it cannot be excluded that more general differences exist with regard to motivation towards interventions or health issues in men and women, as have been described in the literature (e.g., Ek, 2013). In future studies, motivation for or engagement in cognitive interventions could be controlled for by integrating for instance the number of training sessions completed as a covariate to the analyses. Unfortunately, owing to the study design and the analyses of already-existing data from a database, no detailed information was available for the present study. Other variables that had not been assessed for this study but should be focused as covariates in future studies are, for example, marriage status (e.g., Van Gelder et al., 2006), job information (e.g., Stern, 2009), or comorbidities such as cardiovascular diseases or risk factors (e.g., Lopez et al., 2003). Fifth, as data sets of participants were included who participated in at least 8 out of 12 sessions, the variability of intensity of training might have had an impact on the effects. However, as absence from the sessions was an exception in this highly motivated group of individuals and only occurred when they had urgent other appointments, variability was little. Furthermore, a selection of those individuals who participated in all 12 sessions would probably have led to an even stronger selection bias. Sixth, only short-term effects directly after the training were examined in our study and it remains unclear whether the reported effects are stable over time. However, this first investigation that indicates possible sex-specific short-term training gains in MCI patients can be regarded as a good starting point and justification for future research. Further investigation should replicate short-term effects but should also include follow-up assessments to investigate whether the sex-specific cognitive gains are stable over time. Finally, a more general challenge of training studies that should be noted is the question on how to evaluate whether effects are clinically relevant. One option is to determine the statistical reliability of changes in a person’s test score using the “reliable change indices” (RCIs; e.g., as indicated in the systematic review from Stein, Luppa, Brähler, König, & Riedel-Heller, 2010) – which unfortunately are not yet available for the outcome measures used in this study. Whether our results have clinical relevance in terms of further prevention or delay of cognitive decline or development of dysfunctions in activities of daily living will have to be determined in future studies. This is the first study to investigate sex differences in cognitive gains of female and male amnestic MCI patients after a cognitive training. Our results indicate that sex is an influencing factor on cognitive training effects in amnestic MCI patients. Especially in the domains of verbal episodic and working memory we found female MCI patients to benefit significantly more than men. Underlining the clinical relevance of these results, deficits in episodic and working memory have been described as predictive for progression to Alzheimer’s dementia in patients with MCI (Belleville, Sylvain-Roy, De Boysson, & Ménard, 2008). Subjective memory complaints and objectively assessed mnemonic deficits are the main symptoms of amnestic MCI. Accordingly, in our study especially this highly sensitive mnestic domain was variably trainable in women and men. Thus, our preliminary findings support the need for sex-sensitive evaluations of cognitive training in patients with amnestic MCI. Furthermore, in line with Aguirre et al. (2013), our study

Aging, Neuropsychology, and Cognition

15

indicates that an adaption of cognitive training to specific female and male resources might be important for improving cognitive functions. More research with larger sample sizes to support these conclusions is needed. In summary, as also recommended by Baron et al. (2015), future studies should include analyses of sex differences in the evaluation of cognitive training effects and should compare different sex-adapted training forms in randomized controlled trials. In addition, the investigation of underlying mechanisms (e.g.,with brain imaging techniques or estrogen -level analysis) of sex-specific cognitive training gains is important.

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Acknowledgments We thank all participants for their interest in the study, Bettina Grittner, Katrin Müller, Sonja Niessen, Marius Schlegel, and Annabell Zink for their help with data collection. This research was conducted at the University Hospital of Cologne.

Disclosure statement Elke Kalbe, Stephanie Kaesberg, and Josef Kessler are authors of the NEUROvitalis program but do not receive royalties.

Funding This research was supported by budget resources of the University Hospital of Cologne.

References Aguirre, E., Hoare, Z., Streater, A., Spector, A., Woods, B., Hoe, J., & Orrell, M. (2013). Cognitive stimulation therapy (CST) for people with dementia – Who benefits most?. International Journal of Geriatric Psychiatry, 28, 284–290. doi:10.1002/gps.3823 Baller, G., Kalbe, E., Kaesberg, S., & Kessler, J. (2009). NEUROvitalis. Ein neuropsychologisches Gruppenprogramm zur Förderung der geistigen Leistungsfähigkeit. Köln: ProLog. Baron, S., Ulstein, I., & Werheid, K. (2015). Psychosocial interventions in Alzheimer’s disease and amnestic mild cognitive impairment: Evidence for gender bias in clinical trials. Aging & Mental Health, 19, 290–305. doi:10.1080/13607863.2014.938601 Beinhoff, U., Tumani, H., Brettschneider, J., Bittner, D., & Riepe, M. W. (2008). Gender-specificities in Alzheimer’s disease and mild cognitive impairment. Journal of Neurology, 255, 117–122. doi:10.1007/s00415-008-0726-9 Belleville, S., Gilbert, B., Fontaine, F., Gagnon, L., Ménard, E., & Gauthier, S. (2006). Improvement of episodic memory in persons with Mild Cognitive Impairment and healthy older adults: Evidence from a cognitive intervention program. Dementia and Geriatric Cognitive Disorders, 22, 486–499. doi:10.1159/000096316 Belleville, S., Sylvain-Roy, S., De Boysson, C., & Ménard, M.-C. (2008). Characterizing the memory changes in persons with mild cognitive impairment. Progress in Brain Research, 169, 365–375. doi:10.1016/S0079-6123(07)00023-4 Binetti, G., Moretti, D. V., Scalvini, C., Di Giovanni, G., Verzeletti, C., Mazzini, F., . . . Benussi, L. (2013). Predictors of comprehensive stimulation program efficacy in patients with cognitive impairment. Clinical practice recommendations. International Journal of Geriatric Psychiatry, 28, 26–33. doi:10.1002/gps.3785 Boss, L., Kang, D.-H., Marcus, M., & Bergstrom, N. (2014). Endogenous sex hormones and cognitive function in older adults: A systematic review. Western Journal of Nursing Research, 36, 388–426. doi:10.1177/0193945913500566 Bühner, M., & Ziegler, M. (2009). Statistik für Psychologen und Sozialwissenschaftler. München: Pearson Studium.

Downloaded by [Ulster University Library] at 03:51 03 April 2015

16

J. Rahe et al.

Cabeza, R., Dolcos, F., Graham, R., & Nyberg, L. (2002). Similarities and differences in the neural correlates of episodic memory retrieval and working memory. NeuroImage, 16, 317–330. doi:10.1006/nimg.2002.1063 Coffey, C. E., Wilkinson, W. E., Parashos, L. A., Soady, S. A. R., Sullivan, R. J., Patterson, L. J., . . . Djang, W. T. (1992). Quantitative cerebral anatomy of the aging human brain: A cross-sectional study using magnetic resonance imaging. Neurology, 42, 527–536. doi:10.1212/WNL.42.3.527 Cooper, C., Li, R., Lyketsos, C., & Livingston, G. (2013). Treatment for mild cognitive impairment: Systematic review. The British Journal of Psychiatry, 203, 255–264. doi:10.1192/bjp. bp.113.127811 Corrigan, J. D., & Hinkeldey, N. S. (1987). Relationships between Parts A and B of the Trail Making Test. Journal of Clinical Psychology, 43, 402–409. doi:10.1002/1097-4679(198707) 43:43.0.CO;2-E Daneman, M. (1991). Working memory as a predictor of verbal fluency. Journal of Psycholinguistic Research, 20, 445–464. doi:10.1007/bf01067637 De Frias, C. M., Nilsson, L.-G., & Herlitz, A. (2006). Sex differences in cognition are stable over a 10-year period in adulthood and old age. Aging, Neuropsychology, and Cognition, 13, 574–587. doi:10.1080/13825580600678418 Duff, K., Schoenberg, M. R., Mold, J. W., Scott, J. G., & Adams, R. L. (2011). Gender differences on the repeatable battery for the assessment of neuropsychological status subtests in older adults: Baseline and retest data. Journal of Clinical and Experimental Neuropsychology, 33, 448–455. doi:10.1080/13803395.2010.533156 Eberling, J. L., Wu, C., Haan, M. N., Mungas, D., Buonocore, M., & Jagust, W. J. (2003). Preliminary evidence that estrogen protects against age-related hippocampal atrophy. Neurobiology of Aging, 24, 725–732. doi:10.1016/S0197-4580(02)00056-8 Ek, S. (2013). Gender differences in health information behaviour: A Finnish population-based survey. Health Promotion International. Advance online publication. doi:10.1093/heapro/ dat063. Retrieved from http://heapro.oxfordjournals.org/content/early/2013/08/28/heapro. dat063.full Field, A. (2009). Discovering statistics using SPSS (3rd ed.). Los Angeles, CA: SAGE Publications. Fjell, A. M., Westlye, L. T., Amlien, I., Espeseth, T., Reinvang, I., Raz, N., . . . Walhovd, K. B. (2009). Minute effects of sex on the aging brain: A multisample magnetic resonance imaging study of healthy aging and Alzheimer’s disease. The Journal of Neuroscience, 29, 8774–8783. doi:10.1523/JNEUROSCI.0115-09.2009 Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). Mini-mental state – A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189–198. doi:10.1016/0022-3956(75)90026-6 Gates, N. J., Sachdev, P. S., Fiatarone Singh, M. A., & Valenzuela, M. (2011). Cognitive and memory training in adults at risk of dementia: A systematic review. BMC Geriatrics, 11, 55. doi:10.1186/1471-2318-11-55 Gerstorf, D., Herlitz, A., & Smith, J. (2006). Stability of sex differences in cognition in advanced old age: The role of education and attrition. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 61, P245–P249. doi:10.1093/geronb/61.4.P245 Gong, G., He, Y., & Evans, A. C. (2011). Brain connectivity: Gender makes a difference. The Neuroscientist, 17, 575–591. doi:10.1177/1073858410386492 Günther, V. K., Schäfer, P., Holzner, B. J., & Kemmler, G. W. (2003). Long-term improvements in cognitive performance through computer-assisted cognitive training: A pilot study in a residential home for older people. Aging and Mental Health, 7, 200–206. doi:10.1080/ 1360786031000101175 Gur, R. C., Mozley, P. D., Resnick, S. M., Gottlieb, G. L., Kohn, M., Zimmerman, R., . . . Berretta, D. (1991). Gender differences in age effect on brain atrophy measured by magnetic resonance imaging.. Proceedings of the National Academy of Sciences of the United States of America, 88, 2845–2849. doi:10.1073/pnas.88.7.2845 Hautzinger, M., Keller, F., & Kühner, C. (2009). BDI-II. Beckdepressions-inventar. Revision (2nd ed.). Frankfurt: Pearson. Henderson, V. W., Watt, L., & Buckwalter, J. G. (1996). Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease. Psychoneuroendocrinology, 21, 421–430. doi:10.1016/0306-4530(95)00060-7

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Aging, Neuropsychology, and Cognition

17

Herlitz, A., Nilsson, L.-G., & Bäckman, L. (1997). Gender differences in episodic memory. Memory & Cognition, 25, 801–811. doi:10.3758/bf03211324 Herlitz, A., & Yonker, J. E. (2002). Sex differences in episodic memory: The influence of intelligence. Journal of Clinical and Experimental Neuropsychology, 24, 107–114. doi:10.1076/jcen.24.1.107.970 Huckans, M., Hutson, L., Twamley, E., Jak, A., Kaye, J., & Storzbach, D. (2013). Efficacy of cognitive rehabilitation therapies for Mild Cognitive Impairment (MCI) in older adults: Working toward a theoretical model and evidence-based interventions. Neuropsychology Review, 23, 63–80. doi:10.1007/s11065-013-9230-9 Jean, L., Bergeron, M.-È., Thivierge, S., & Simard, M. (2010). Cognitive intervention programs for individuals with mild cognitive impairment: Systematic review of the literature. The American Journal of Geriatric Psychiatry, 18, 281–296. doi:10.1097/JGP.0b013e3181c37ce9 Kalbe, E., Kessler, J., Calabrese, P., Smith, R., Passmore, A. P., Brand, M., & Bullock, R. (2004). DemTect: A new, sensitive cognitive screening test to support the diagnosis of mild cognitive impairment and early dementia. International Journal of Geriatric Psychiatry, 19, 136–143. doi:10.1002/gps.1042 Kessler, J., Calabrese, P., & Kalbe, E. (2010). DemTect-B: Ein Äquivalenztest zum kognitiven Screening DemTect-A®. Fortschritte der Neurologie Psychiatrie, 78, 532–535. doi:10.1055/s0029-1245452 Konsztowicz, S., Anton, J., Crane, J., Moafmashhadi, P., & Koski, L. (2013). A pilot study of training and compensation interventions for mild cognitive impairment. Dementia and Geriatric Cognitive Disorders Extra, 3, 192–201. doi:10.1159/000350026 Kramer, J. H., Yaffe, K., Lengenfelder, J., & Delis, D. C. (2003). Age and gender interactions on verbal memory performance. Journal of the International Neuropsychological Society, 9, 97–102. doi:10.1017/S1355617703910113 Kurz, A., Thöne-Otto, A., Cramer, B., Egert, S., Frölich, L., Gertz, H.-J., . . . Werheid, K. (2012). CORDIAL: Cognitive rehabilitation and cognitive-behavioral treatment for early dementia in Alzheimer disease: A multicenter, randomized, controlled trial. Alzheimer Disease & Associated Disorders, 26, 246–253. doi:10.1097/WAD.0b013e318231e46e Lamar, M., Resnick, S. M., & Zonderman, A. B. (2003). Longitudinal changes in verbal memory in older adults: Distinguishing the effects of age from repeat testing. Neurology, 60, 82–86. doi:10.1212/WNL.60.1.82 Larrabee, G. J., & Crook, T. H. (1993). Do men show more rapid age-associated decline in simulated everyday verbal memory than do women?. Psychology and Aging, 8, 68–71. doi:10.1037/0882-7974.8.1.68 Le Carret, N., Auriacombe, S., Letenneur, L., Bergua, V., Dartigues, J.-F., & Fabrigoule, C. (2005). Influence of education on the pattern of cognitive deterioration in AD patients: The cognitive reserve hypothesis. Brain and Cognition, 57, 120–126. doi:10.1016/j.bandc.2004.08.031 Lewin, C., Wolgers, G., & Herlitz, A. (2001). Sex differences favoring women in verbal but not in visuospatial episodic memory. Neuropsychology, 15, 165–173. doi:10.1037/0894-4105.15.2.165 Lezak, M. D., Howieson, D. B., & Loring, D. W. (2004). Neuropsychological assessment (4th ed.). Oxford: Oxford University Press. Li, H., Li, J., Li, N., Li, B., Wang, P., & Zhou, T. (2011). Cognitive intervention for persons with mild cognitive impairment: A meta-analysis. Ageing Research Reviews, 10, 285–296. doi:10.1016/j.arr.2010.11.003 Li, R., & Singh, M. (2014). Sex differences in cognitive impairment and Alzheimer’s disease. Frontiers in Neuroendocrinology, 35, 385–403. doi:10.1016/j.yfrne.2014.01.002 Lopez, O. L., Jagust, W. J., Dulberg, C., Becker, J. T., DeKosky, S. T., Fitzpatrick, A., . . . Kuller, L. H. (2003). Risk factors for mild cognitive impairment in the cardiovascular health study cognition study: Part 2. Archives of Neurology, 60, 1394–1399. doi:10.1001/archneur.60. 10.1394 Martin, M., Clare, L., Altgassen, A. M., Cameron, M. H., & Zehnder, F. (2011). Cognition-based interventions for healthy older people and people with mild cognitive impairment. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD006220.pub2 Masters, M. S., & Sanders, B. (1993). Is the gender difference in mental rotation disappearing?. Behavior Genetics, 23, 337–341. doi:10.1007/BF01067434

Downloaded by [Ulster University Library] at 03:51 03 April 2015

18

J. Rahe et al.

Mitchell, A. J., & Shiri-Feshki, M. (2009). Rate of progression of Mild Cognitive Impairment to dementia – Meta-analysis of 41 robust inception cohort studies. Acta Psychiatrica Scandinavica, 119, 252–265. doi:10.1111/j.1600-0447.2008.01326.x Modrego, P. J. (2006). Predictors of conversion to dementia of probable Alzheimer type in patients with mild cognitive impairment. Current Alzheimer Research, 3, 161–170. doi:10.2174/ 156720506776383103 Moreno-Martínez, F. J., Laws, K. R., & Schulz, J. (2008). The impact of dementia, age and sex on category fluency: Greater deficits in women with Alzheimer’s disease. Cortex, 44, 1256–1264. doi:10.1016/j.cortex.2007.11.008 Munro, C. A., Winicki, J. M., Schretlen, D. J., Gower, E. W., Turano, K. A., Muñoz, B., . . . West, S. K. (2012). Sex differences in cognition in healthy elderly individuals. Aging, Neuropsychology, and Cognition, 19, 759–768. doi:10.1080/13825585.2012.690366 Olazaran, J., Muniz, R., Reisberg, B., Pena-Casanova, J., Del Ser, T., Cruz-Jentoft, A. J., . . . Sevilla, C. (2004). Benefits of cognitive-motor intervention in MCI and mild to moderate Alzheimer disease. Neurology, 63, 2348–2353. doi:10.1212/01.wnl.0000147478.03911.28 Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256, 183–194. doi:10.1111/j.1365-2796.2004.01388.x Petersen, R. C. (2011). Mild cognitive impairment. New England Journal of Medicine, 364, 2227–2234. doi:10.1056/NEJMcp0910237 Petersen, R. C., Doody, R., Kurz, A., Mohs, R. C., Morris, J. C., Rabins, P. V., . . . Winblad, B. (2001). Current concepts in mild cognitive impairment. Archives of Neurology, 58, 1985–1992. doi:10.1001/archneur.58.12.1985 Proust-Lima, C., Amieva, H., Letenneur, L., Orgogozo, J.-M., Jacqmin-Gadda, H., & Dartigues, J.F. (2008). Gender and education impact on brain aging: A general cognitive factor approach. Psychology and Aging, 23, 608–620. doi:10.1037/a0012838 Pruessner, J. C., Collins, D. L., Pruessner, M., & Evans, A. C. (2001). Age and gender predict volume decline in the anterior and posterior hippocampus in early adulthood. The Journal of Neuroscience, 21, 194–200. Raz, N., Gunning-Dixon, F., Head, D., Rodrigue, K. M., Williamson, A., & Acker, J. D. (2004). Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: Replicability of regional differences in volume. Neurobiology of Aging, 25, 377–396. doi:10.1016/s0197-4580 (03)00118-0 Reijnders, J., Van Heugten, C., & Van Boxtel, M. (2013). Cognitive interventions in healthy older adults and people with mild cognitive impairment: A systematic review. Ageing Research Reviews, 12, 263–275. doi:10.1016/j.arr.2012.07.003 Reitan, R. M., & Wolfson, D. (1993). The Halstead-Reitan Neuropsychological Test Battery (2nd ed.). Tucson, AZ: Neuropsychology Press. Ropele, S., Enzinger, C., Sollinger, M., Langkammer, C., Wallner-Blazek, M., Schmidt, R., & Fazekas, F. (2010). The impact of sex and vascular risk factors on brain tissue changes with aging: Magnetization transfer imaging results of the Austrian stroke prevention study. American Journal of Neuroradiology, 31, 1297–1301. doi:10.3174/ajnr.A2042 Rosen, W. G., Mohs, R. C., & Davis, K. L. (1984). A new rating scale for Alzheimer’s disease. The American Journal of Psychiatry, 141, 1356–1364. doi:10.1176/ajp.141.11.1356 Schaaf, A., Kessler, J., Grond, M., & Fink, G. R. (1992). Memo-Test Manual. Weinheim: Beltz Test. Scheurich, A., Muller, M. J., Siessmeier, T., Bartenstein, P., Schmidt, L. G., & Fellgiebel, A. (2005). Validating the DemTect with 18-fluoro-2-deoxy-glucose positron emission tomography as a sensitive neuropsychological screening test for early Alzheimer disease in patients of a memory clinic. Dement Geriatr Cogn Disord, 20, 271–277. doi:10.1159/000088248 Simon, S. S., Yokomizo, J. E., & Bottino, C. M. C. (2012). Cognitive intervention in amnestic mild cognitive impairment: A systematic review. Neuroscience & Biobehavioral Reviews, 36, 1163–1178. doi:10.1016/j.neubiorev.2012.01.007 Spreen, O., & Strauss, E. (2006). A compendium of neuropsychological tests: Administration, norms and commentary (3rd ed.). New York, NY: Oxford University Press. Stein, J., Luppa, M., Brähler, E., König, H.-H., & Riedel-Heller, S. G. (2010). The assessment of changes in cognitive functioning: Reliable change indices for neuropsychological instruments in the elderly – A systematic review. Dementia and Geriatric Cognitive Disorders, 29, 275–286. doi:10.1159/000289779

Downloaded by [Ulster University Library] at 03:51 03 April 2015

Aging, Neuropsychology, and Cognition

19

Stern, Y. (2009). Cognitive reserve. Neuropsychologia, 47, 2015–2028. doi:10.1016/j. neuropsychologia.2009.03.004 Suzuki, T., Shimada, H., Makizako, H., Doi, T., Yoshida, D., Ito, K., . . . Aleman, A. (2013). A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. Plos One, 8, e61483. doi:10.1371/journal.pone.0061483 Teixeira, C. V. L., Gobbi, L. T. B., Corazza, D. I., Stella, F., Costa, J. L. R., & Gobbi, S. (2012). Non-pharmacological interventions on cognitive functions in older people with Mild Cognitive Impairment (MCI). Archives of Gerontology and Geriatrics, 54, 175–180. doi:10.1016/j. archger.2011.02.014 Van Exel, E., Gussekloo, J., De Craen, A. J. M., Bootsma-Van Der Wiel, A., Houx, P., Knook, D. L., & Westendorp, R. G. J. (2001). Cognitive function in the oldest old: Women perform better than men. Journal of Neurology, Neurosurgery & Psychiatry, 71, 29–32. doi:10.1136/jnnp.71.1.29 Van Gelder, B. M., Tijhuis, M., Kalmijn, S., Giampaoli, S., Nissinen, A., & Kromhout, D. (2006). Marital status and living situation during a 5-year period are associated with a subsequent 10-year cognitive decline in older men: The FINE Study. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 61, P213–P219. doi:10.1093/geronb/61.4.P213 Verghese, J., Kuslansky, G., Katz, M. J., Sliwinski, M., Crystal, H. A., Buschke, H., & Lipton, R. B. (2000). Cognitive performance in surgically menopausal women on estrogen. Neurology, 55, 872–874. doi:10.1212/WNL.55.6.872 Wahlin, Å., MacDonald, S. W. S., Defrias, C. M., Nilsson, L.-G., & Dixon, R. A. (2006). How do health and biological age influence chronological age and sex differences in cognitive aging: Moderating, mediating, or both? Psychology and Aging, 21, 318–332. doi:10.1037/ 0882-7974.21.2.318 Wiederholt, W. C., Cahn, D., Butters, N. M., Salmon, D. P., Kritz-Silverstein, D., & Barrett-Connor, E. (1993). Effects of age, gender, and education on selected neuropsychological tests in an elderly community cohort. Journal of the American Geriatrics Society, 41, 639–647.