The long-term relation between physical activity and executive function in the Rotterdam Study.

BACKGROUND: Research on the association between physical inactivity and cognitive decline and dementia is dominated by studies with short-term follow-up, that might be biased by reverse causality. OBJECTIVE: Investigate the long-term association between physical activity, cognition, and the rate of age-associated cognitive decline. METHODS: We investigated the association between late-life physical activity and executive functioning and rate of decline of executive abilities during follow-up of up to 16 years, in 3553 participants of the prospective Rotterdam Study cohort. Measurement took place in 1997-1999, 2002-2004, 2009-2011, and 2014-2015. RESULTS: At baseline (age ± 72 years), higher levels of physical activity were associated with higher levels of executive functioning (adjusted mean difference = 0.03, 95% CI: 0.00 ; 0.06, p = 0.03). This difference remained intact up to 16 years of follow-up. The level of physical activity at baseline was unrelated to the rate of decline of executive abilities over time, in the whole group (adjusted mean difference in changetime*physical activity = 0.00, 95% CI: -0.00 ; 0.01, p = 0.31). However, stratification by APOE genotype showed that the accelerated decline of executive abilities observed in those with the ApoE-ε4 allele might be attenuated by higher levels of physical activity in late adulthood (ApoE-ε4 carriers: Btime*physical activity = 0.01, 95% CI: 0.00 ; 0.01, p = 0.03). CONCLUSION: Higher levels of physical activity in late adulthood are related to higher levels of executive functioning, up to 16 years of follow-up. Accelerated decline of executive abilities observed in those with the ApoE-ε4 allele might be mitigated by higher levels of physical activity.

Effects of binaural and monaural beat stimulation on attention and EEG.

Nowadays a popular technique to improve mood and cognition is auditory beat stimulation (ABS), which is thought to induce a frequency-following response of brainwaves. The main types of ABS are monaural beats (MB) and binaural beats (BB). BB involves the presentation of a specific frequency to one ear and another frequency to the other ear which may induce neural entrainment. A difference between the frequencies of 40 Hz is assumed to improve cognition. The present study examined the effect of 40 Hz binaural beats (BB) and monaural beats (MB) on attention and electroencephalography (EEG). A total of 25 first-year psychology students (11 males, 14 females) performed a Flanker task while EEG was recorded during the 5 min-presentation of pink noise (PN), MB and BB. With respect to attention, as measured by the Flanker task, the number of false responses in the BB condition was smaller than that in the PN condition while the number of false responses in the MB condition was larger as compared to the PN condition. As there was no association of BB with a consistent increase in absolute 40 or 45 Hz power compared to PN or MB, EEG recordings could not confirm the hypothesized neural entrainment in the brain. Overall, the current findings show that listening to 40 Hz BB improves attention but do not show the occurrence of neural entrainment. Future research is recommended to include a larger sample, to use a broader cognitive test battery and to present auditory beats with a longer duration.

Psychological well-being and illness perceptions in patients with hypopituitarism.

OBJECTIVE: The primary aim of the current study was to objectify a spectrum of persisting subjective psychological complaints in patients with hypopituitarism, at least six months after normalizing of the hormonal disturbances. Also, gender differences on these outcomes were investigated. The secondary aim was to identify illness perceptions and causal attributions within this patient group. METHODS: A total of 42 adult participants (60% females) with treated hypopituitarism once filled out a number of psychological questionnaires. The Profile of Mood States (POMS) and the Hospital Anxiety and Depression Scale (HADS) assessed mood and the Symptom Checklist-90 (SCL-90) and the Work and Social Adjustment Scale (WSAS) assessed well-being. Illness perceptions were identified using the Illness Perceptions Questionnaire-Brief Dutch Language Version (IPQ-B DLV) and causal attributions by using the Causal Attribution List (CAL). Patient outcomes were compared to reference values of healthy norm groups. RESULTS: Participants scored significantly worse on the POMS depression, anger, fatigue and tension subscales, the SCL-90 psychoneuroticism, depression, inadequacy of thinking and acting and sleeping problems subscales and all subscales of the WSAS when compared to reference data. Women also scored worse on depression (HADS) and somatic symptoms (SCL-90). Compared to other illnesses, patients with hypopituitarism have more negative and realistic illness perceptions on consequences, timeline, identity and emotions. Participants attributed their complaints more to physical causes than psychological causes. CONCLUSION: Despite normalization of hormonal disturbances, patients with hypopituitarism in general can still experience problems during daily living, such as negative mood states and a decreased psychological well-being.

Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency.

BACKGROUND: The aim of the present study was to investigate the effect of low-normal and high-normal levels of IGF-1 in growth hormone (GH) deficient adults on cognition and wellbeing during GH treatment. METHODS: A randomized, open-label, clinical trial including 32 subjects receiving GH therapy for at least 1 year. Subjects were randomized to receive either a decrease (IGF-1 target level of - 2 to - 1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Memory was measured by the Cambridge Neuropsychological Test Automated Battery, selecting the Pattern Recognition Memory task and the Spatial Working Memory. Wellbeing was measured as mood by the Profile of Moods States questionnaire, and quality of life by the Nottingham Health Profile and QoL Assessment in GH Deficiency in Adults questionnaires. RESULTS: Data from 30 subjects (65.6% male, mean age 46.6 (9.9 SD) years), who fulfilled the target levels, were analyzed. Females in the low dose treatment arm were found to have a better working memory and a better strategic memory control after 24 weeks as opposed to the females in the high treatment arm. With respect to mood, the decrease in IGF-1 levels in females within the low treatment arm was associated with more fatigue and less vigor. CONCLUSIONS: The adjustment of GH dose in female patients seems to have a narrow window. A dose too high may impair prefrontal cognitive functioning, while a dose too low may result in decreased vigor. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT01877512.

Disrupted brain network topology in Parkinson's disease: a longitudinal magnetoencephalography study.

Although alterations in resting-state functional connectivity between brain regions have previously been reported in Parkinson's disease, the spatial organization of these changes remains largely unknown. Here, we longitudinally studied brain network topology in Parkinson's disease in relation to clinical measures of disease progression, using magnetoencephalography and concepts from graph theory. We characterized whole-brain functional networks by means of a standard graph analysis approach, measuring clustering coefficient and shortest path length, as well as the construction of a minimum spanning tree, a novel approach that allows a unique and unbiased characterization of brain networks. We observed that brain networks in early stage untreated patients displayed lower local clustering with preserved path length in the delta frequency band in comparison to controls. Longitudinal analysis over a 4-year period in a larger group of patients showed a progressive decrease in local clustering in multiple frequency bands together with a decrease in path length in the alpha2 frequency band. In addition, minimum spanning tree analysis revealed a decentralized and less integrated network configuration in early stage, untreated Parkinson's disease that also progressed over time. Moreover, the longitudinal changes in network topology identified with both techniques were associated with deteriorating motor function and cognitive performance. Our results indicate that impaired local efficiency and network decentralization are very early features of Parkinson's disease that continue to progress over time, together with reductions in global efficiency. As these network changes appear to reflect clinically relevant phenomena, they hold promise as markers of disease progression.

The effects of a moderate physical activity intervention on physical fitness and cognition in healthy elderly with low levels of physical activity: a randomized controlled trial.

BACKGROUND: Increasing physical activity is one of the most promising and challenging interventions to delay or prevent cognitive decline and dementia. METHODS: We conducted a randomized controlled trial to assess the effects of a physical activity intervention, aimed at increasing step count, in elderly with low levels of physical activity on measures of strength, balance, aerobic capacity, and cognition. Participants were assigned to 9 months of exercise counseling or active control. RESULTS: The intention-to-treat analyses show that the intervention, compared to control, increases the level of physical activity, but has no significant effect on physical fitness and cognition. Those who increased their physical activity with 35% or more show significant improvements in aerobic capacity, gait speed, verbal memory, executive functioning, and global cognition, compared to those who did not achieve a 35% increase. LIMITATIONS: The number of participants that achieved the intended improvement was lower than expected. CONCLUSION: Responder analyses suggest an improvement of physical fitness and cognition in those who achieved an increase in physical activity of at least 35%. TRIAL REGISTRATION: The trial protocol is registered at the Dutch Trial Register NL5675, August 1, 2016.

Plasma Brain-Derived Neurotropic Factor Levels Are Associated with Aging and Smoking But Not with Future Dementia in the Rotterdam Study.

BACKGROUND: Brain-derived neurotropic factor (BDNF) plays a vital role in neuronal survival and plasticity and facilitates long-term potentiation, essential for memory. Alterations in BDNF signaling have been associated with cognitive impairment, dementia, and Alzheimer's disease. Although peripheral BDNF levels are reduced in dementia patients, it is unclear whether changes in BDNF levels precede or follow dementia onset. OBJECTIVE: In the present study, we examined the association between BDNF plasma levels and dementia risk over a follow-up period of up to 16 years. METHODS: Plasma BDNF levels were assessed in 758 participants of the Rotterdam Study. Dementia was assessed from baseline (1997-1999) to follow-up until January 2016. Associations of plasma BDNF and incident dementia were assessed with Cox proportional hazards models, adjusted for age and sex. Associations between plasma BDNF and lifestyle and metabolic factors are investigated using linear regression. RESULTS: During a follow up of 3,286 person-years, 131 participants developed dementia, of whom 104 had Alzheimer's disease. We did not find an association between plasma BDNF and risk of dementia (adjusted hazard ratio 0.99; 95%CI 0.84-1.16). BDNF levels were positively associated with age (B = 0.003, SD = 0.001, p = 0.002), smoking (B = 0.08, SE = 0.01, p = < 0.001), and female sex (B = 0.03, SE = 0.01, p = 0.03), but not with physical activity level (B = -0.01, SE = 0.01, p = 0.06). CONCLUSION: The findings suggest that peripheral BDNF levels are not associated with an increased risk of dementia.

Impaired neuropsychological functioning in patients with hypopituitarism.

Background: Treatment of pituitary pathology mostly does not result in complete recovery of impairment in cognitive functioning. The primary aim of the current study was to assess cognitive impairment in patients with stable replacement therapy for hypopituitarism during the last 6 months prior to inclusion. It was expected that patients showed subjective and objective subnormal scores on neuropsychological functioning. Methods: Forty-two patients (40% men, 49 ± 15 years) treated for hypopituitarism conducted a neuropsychological test battery, including the Cognitive Failures Questionnaire (CFQ), 15-Word test (15-WT), Cambridge Neuropsychological Test Automated Battery (CANTAB) Motor Screening Task (MOT), Spatial Working Memory (SWM) and Affective Go/No-go (AGN). Results were compared to reference values of healthy norm groups. Results: Male and female participants scored significantly worse on the CFQ (P < .01, d = 0.91-4.09) and AGN mean correct latency (P < .01, d = 1.66 and 1.29, respectively). Female participants scored significantly worse on 15-WT direct recall (P = .01, d = 0.66), 15-WT delayed recall (P = .01, d = 0.79), SWM total errors (P = .05, d = 0.41), SWM strategy (P = .04, d = 0.43), AGN errors of commission (P = .02, d = 0.56) and omission (P = .04, d = 0.41). Conclusion: This study shows that subjective cognitive functioning is worse in patients treated for hypopituitarism compared to reference data. Also, female participants treated for hypopituitarism score worse on objective aspects of memory and executive functioning compared to reference data. Besides worse focus attention, this objective cognitive impairment was not found in male participants. It is recommended to conduct additional research, which focuses on the design and evaluation of a cognitive remediation therapy, aimed at compensation of impairments in different aspects of memory and executive functioning.

Food-Related Brain Activation Measured by fMRI in Adults with Prader-Willi Syndrome.

(1) Background: Prader-Willi syndrome (PWS) is characterized by hyperphagia, resulting in morbid obesity if not controlled. The primary aim of this study was to investigate whether PWS patients show altered activation of brain areas involved in hunger. As a secondary objective, we assessed whether there is an association between these brain areas and several endocrine and metabolic factors in the fasting state. (2) Methods: 12 PWS adults and 14 healthy controls (siblings) performed a food-related experimental task after an overnight fast while brain activation in regions of interest was measured by functional MRI. (3) Results: In controls, significantly more activation was found in the left insula (p = 0.004) and the bilateral fusiform gyrus (p = 0.003 and 0.013) when the individuals were watching food as compared to non-food pictures, which was absent in PWS patients. Moreover, in PWS adults watching food versus non-food pictures a significant negative correlation for glucose and right amygdala activation (p_fwe = 0.007) as well as a positive correlation for leptin and right anterior hippocampus/amygdala activation (p_fwe = 0.028) was demonstrated. No significant associations for the other hormonal and metabolic factors were found. (4) Conclusions: PWS individuals show aberrant food-related brain activation in the fasting state. Leptin is associated with activation within the neural motivation/reward circuitry, while the opposite is true for glucose.

SPEM dysfunction and general schizotypy as measured by the SSQ: a controlled study.

BACKGROUND: SPEM dysfunction is a well-known phenomenon in schizophrenia. The principal aim of the present study was to examine whether SPEM dysfunction is already observable in subjects scoring high on a specific measure of schizotypy (SSQ General Schizotypy) that was selected because of its intimate relationship with schizophrenic prodromal unfolding. METHODS: Applying ANOVAs, we determined the relationship of subjects' scores on SSQ General Schizotypy and eye movements elicited by targets of different speed. We also examined whether there exists an association between our schizotypy measure and pupil size. RESULTS: We found more SPEM dysfunction in subjects scoring high on SSQ General Schizotypy than in subjects scoring average on that factor, irrespective of the speed of the target. No relationship was found between baseline pupil size and General Schizotypy. CONCLUSION: The present study provides additional evidence that SPEM dysfunction is associated with schizotypic features that precede the onset of schizophrenia and is already observable in general population subjects that show these features.

The Effects of Binaural and Monoaural Beat Stimulation on Cognitive Functioning in Subjects with Different Levels of Emotionality.

Today, binaural and monaural beats are offered over the Internet or by mental health institutes to improve wellbeing or cognitive functioning. This improvement is explained by the assumption that the brain adapts its brainwave frequency to the frequency of the auditory beat. The present study examined the effects of binaural and monaural beat stimulation on attention and working memory in high and low emotional participants. A group of 24 participants (16 females, 8 males) between 19 and 31 years old (M = 22.33, SD = 3.42) performed a Flanker task to measure attention and a Klingberg task to measure working memory while listening to white noise (WN), 40 Hz gamma binaural beat (BB) and 40 Hz gamma monaural beat (MB). Speed of performance on all three levels of difficulty of the Flanker attention task was faster under the BB and MB condition than under WN. No differences were found between BB and MB conditions. With respect to the quality of performance on the Flanker attention task and the Klingberg working memory task no significant differences under the WN, MB, and BB condition were found. Finally, as participants with low or high emotionality did not respond differently to BB and MB under any of the conditions, effects of BB and MB seem similar in high and low emotional participants. The present study supports the notion that faster attention processing may equally be attributed to the influence of BB and MB. Further research is recommended to gain more insight in the role of factors such as duration of stimulation of BB and MB, frequency range, most appropriate carrier tones, and the role of personality traits.

The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study.

BACKGROUND: To reduce the risk of brain damage children with acute lymphoblastic leukaemia (ALL) are nowadays mainly treated with intrathecal chemotherapy (ITC) instead of central nervous system (CNS) radiation therapy (CRT) to prevent CNS relapse. However, chemotherapy may also lead to cognitive deficits. As growth hormone deficiency (GHD) or impaired growth hormone secretion are frequently found in ALL patients treated with cranial radiation therapy and/or chemotherapy, we hypothesized that GH therapy may reduce cognitive deficits in these patients. METHODS: Twenty young adult survivors of childhood ALL with reduced bone mineral density (<-1 SD) and/or low IGF-I SD-scores (<-1 SD) were included in the study. A final group of 13 patients (9 males and 4 females), mean age 23.7 +/- 2.9 years (range 20 - 29.7) completed a 2-year treatment with GH.IQ and neuropsychological performance were assessed at pre-treatment (T1) and after one (T2) and two (T3) years. ANOVA was performed with assessment at T1, T2 and T3 as repeated measurements factor. Relations between test score changes and changes of IGF-I levels were determined by calculating the Pearson correlation coefficient. RESULTS: Scores on the cognitive tests were in the normal range. Verbal short- and long-term memory performance decreased between T1 and T2, and increased between T2 and T3. Performance at T3 was not significantly different from that at T1. Performance for sustained attention improved from T1 to T2 and from T1 to T3. Visual-spatial memory was improved after one year of GH treatment. A significant positive correlation was found for Delta IGF-I (T2-T1) with difference scores of visual-spatial memory (T2-T1 and T3-T1), indicating that IGF-I increase after one year of GH treatment is associated with increase in cognitive-perceptual performance at month 12 and 24. CONCLUSION: Since the level of intellectual functioning of our patient cohort was in the normal range the present finding that GH treatment has negative effects on verbal memory and positive on attention and visual-spatial memory warrants similar studies in other groups of ALL survivors. Also, a lower dose of GH should be determined inducing as much IGF as needed to improve verbal as well as visual cognitive functions. The present findings indicate that more knowledge is needed before GH treatment may be recommended to enhance cognitive functions in ALL survivors.

The relationship between nonverbal cognitive functions and hearing loss.

PURPOSE: This study investigated the relationship between hearing loss and memory and attention when nonverbal, visually presented cognitive tests are used. METHOD: Hearing loss (pure-tone audiometry) and IQ were measured in 30 participants with mild to severe hearing loss. Participants performed cognitive tests of pattern recognition memory, sustained visual attention, and spatial working memory. All cognitive tests were selected from the Cambridge Neuropsychological Test Automated Battery (CANTAB expedio; Cambridge Cognition Ltd., 2002). Regression analyses were performed to examine the relationship between hearing loss and these cognitive measures of memory and attention when controlling for age and IQ. RESULTS: The data indicate that hearing loss was not associated with decreased performance on the memory and attention tests. In contrast, participants with more severe hearing loss made more use of an efficient strategy during performance on the spatial working memory subtest. This result might reflect the more extensive use of working memory in daily life to compensate for the loss of speech information. CONCLUSIONS: The authors conclude that the use of nonverbal tests is essential when testing cognitive functions of individuals with hearing loss.

Abnormal susceptibility to distracters hinders perception in early stage Parkinson's disease: a controlled study.

BACKGROUND: One of the perceptual abnormalities observed in Parkinson's disease (PD) is a deficit in the suppression of reflexive saccades that are automatically triggered by the onset of a peripheral target. Impairment of substantia nigra function is thought to lead to this reduced ability to suppress reflexive saccades. METHODS: The present study examined whether this perceptual deficit is also present in early stage PD when using hardly noticeable task-irrelevant stimuli. Eleven non-demented de novo, untreated PD patients (mean age 57 yr, range 44-70) participated in the study as well as 12 age-matched controls. Performance on an 'oculomotor capture' task, in which in half of the trials an irrelevant stimulus with sudden onset was added to the display, was compared between patients and controls. Analysis of variance (ANOVA) was performed with group (patients/controls) and age (< 61 yrs/> or = 61 yrs) as independent factors and type of trial (control/distracter) as repeated measurements factor. The factor sex was used as covariate. RESULTS: With respect to Reaction Time (RT), a significant interaction between group and condition was found. RTs increased under the 'irrelevant stimulus' condition in both groups, the patients exhibiting a significantly larger increase in RTs than the control group. Also, a significant interaction effect between group and condition for number of correct responses was found. The number of correct responses was reduced in the onset distracter condition, the reduction being larger in the patients. In the patient group, contrary to the control group, a higher age was associated with fewer correct responses at baseline and in the onset distracter condition, suggesting that perceptual functions in PD are highly susceptible to the effects of ageing. The increased reaction times and larger number of incorrect responses of the PD patients in the onset distracter condition may be related to impairments of substantia nigra function and lower brain stem. CONCLUSION: The capture task seems to be a sensitive instrument to detect early perceptual deficits in PD. The magnitude of the observed deficits suggests that perceptual functions in early stage PD are so substantially impaired that this may interfere with daily activities.

Impaired quality of life in hypopituitary adults with growth hormone deficiency : can somatropin replacement therapy help?

It is generally known that growth hormone (GH)-deficient patients experience emotional instability, reduced energy, sleep disturbances, and problems with (sexual) relationships. GH and insulin-like growth factor-1 (IGF-I) may affect mood parameters by their actions at binding sites in specific brain areas and/or by their effects on dopamine turnover in the brain. Indeed, there is substantial evidence that somatropin (growth hormone) treatment improves the quality of life (QOL) of GH-deficient patients.However, the variety of instruments used makes it questionable whether QOL in particular is affected by somatropin therapy. The measurement of QOL is subject to methodologic difficulties and is frequently not properly distinguished from health status and well-being. QOL ratings are characterized by an emphasis on mental health and health status by an emphasis on physical function, while well-being is concerned with depression, anxiety, and energy levels. Examples of instruments used to measure QOL, health status, and well-being in GH-deficient patients are the Quality of Life-Assessment of Growth Hormone Deficiency in Adults, the Short-Form Health Survey, and the Psychological General Well-Being Schedule, respectively. One additional problem in establishing the effects of somatropin treatment on QOL is that the QOL effects of somatropin treatment may be different for patients with isolated GH deficiency (GHD) and those with multiple pituitary hormone deficiencies.Previously, in order to answer the question of whether somatropin therapy improves mood status in GH-deficient patients, we conducted a meta-analysis comparing somatropin treatment effects relative to baseline and placebo. At 3, 6, and 12 months of somatropin replacement the mood status of GH-deficient patients improved with decreasing effect sizes over time (d = 0.81, 0.55, and 0.29, respectively) from baseline. However, the median somatropin treatment period of 6 months did not improve mood status more than placebo. In a second analysis we classified the questionnaires into those on QOL, those on health status, and those on well-being, respectively, and analyzed the separate effects of pooled treatment durations of about 9 months. Somatropin replacement improved QOL with a small effect size (d = 0.18), well-being with a medium effect size (d = 0.47), and health status with a small effect size (d = 0.26).Although the separate effects of somatropin on QOL, health status, and well-being could not be compared to placebo, we concluded that somatropin treatment most likely plays a role in improving the well-being of patients with GHD. This conclusion is based on correlations that have been found between IGF-I levels and parameters of well-being, such as anxiety and depression.

The Effects of Physical Activity and Fitness in Adolescence on Cognition in Adulthood and the Role of Insulin-Like Growth Factor I.

BACKGROUND: Physical activity and fitness in adolescence may improve cognition in adulthood by increasing insulin-like growth factor I (IGF-I). METHODS: As part of the Amsterdam Growth and Health Longitudinal Study, following subjects from age 13 to 42 years, physical activity and fitness of 303 subjects were assessed annually between the ages 13 to 16. At mean age 36, physical activity, fitness and IGF-I were measured. At mean age 42, IGF-I and cognitive factors (ie, executive functioning and visual-spatial memory) were measured. The linear regression of physical activity and fitness in adolescence and IGF-I in adulthood on cognitive scores in adulthood was investigated. RESULTS: A significant association was found in males between physical activity in adolescence and executive function in adulthood (Spatial Working Memory Between Errors: ß = -.18, B = -.13, 95% CI = -.259 to -.010; Spatial Working Memory Strategy: ß = -.20, B = -.08, 95% CI = -.147 to -.014). No association between physical activity or fitness in adolescence and cognitive function in adulthood was found in females, nor any intermediate role for IGF-I in either sex. CONCLUSIONS: The results suggest a stimulating effect of adolescent physical activity in males on executive functions in adulthood, emphasizing the importance of an active lifestyle among adolescent males.

Effect of an enriched drink on cognitive function in frail elderly persons.

BACKGROUND: Many elderly persons report that they have difficulties learning new things and remembering names, plans, and conversations. Because decreased cognitive function in elderly persons is potentially related to their poor nutritional status, provision of essential nutrients may improve cognitive function. The authors wanted to determine whether consumption of an enriched drink, including moderate doses of all essential micronutrients, improves cognitive function in frail elderly persons. METHODS: Frail, white adults (n=101) who were aged 65 years or older with a body mass index

Differential effect sizes of growth hormone replacement on Quality of Life, well-being and health status in growth hormone deficient patients: a meta-analysis.

BACKGROUND: Patients with growth hormone deficiency (GHD) frequently report to suffer from an impaired Quality of Life (QoL) and growth hormone (GH) substitution is found to improve this. However, the same test may be used for measuring QoL, well-being or health status in different studies. QoL has been defined as the subjective appraisal of one's current life based primarily on psychological function. The most important in the appraisal of well-being is mental function and concerning health status patients evaluate physical function as most important. To differentiate the effects of GH replacement on psychological variables in patients with GHD we carried out a number of meta-analyses, classifying questionnaires into instruments measuring QoL, psychological well-being and health status. METHODS: We searched the electronic databases PUBMED and PiCarta from 1985 to 2004. Studies were included that evaluated the effect of GH on patient-reported outcomes in adults with GHD (aged 18 years and above). According to generally accepted definitions we classified the questionnaires as instruments measuring QoL, well-being and health status. By means of meta-analyses the average effect size (d) for QoL, well-being and health status was calculated. RESULTS AND DISCUSSION: Based on open studies GH replacement is found to improve QoL with a small effect size (d = 0.18), well-being with a medium effect size (d = 0.47) and health status with a small effect size (d = 0.26). As the effect size of well-being is most pronounced the generally reported effects of GH replacement on QoL may be overestimated and actually reflect the effect on well-being. CONCLUSION: To get more insight in the specific psychological effects of GH treatment it is recommended that instruments selected for these studies should be more consistently classified as instruments measuring QoL, well-being or health status.

Cognitive functioning during long-term tamoxifen treatment in postmenopausal women with breast cancer.

OBJECTIVE: Endocrine therapy is widely used-often for many years-in women with breast cancer. Yet little is known about cognitive functioning after long-term use of tamoxifen. We examine cognitive sequelae, approximately 3 years after diagnosis, in postmenopausal women with breast cancer who were treated with adjuvant tamoxifen. METHODS: Data from participants who underwent surgical operation with or without radiotherapy, participants who received adjuvant tamoxifen, and healthy controls were collected. Neuropsychological tests were administered, and participants completed questionnaires on health-related quality of life (Quality of Life Questionnaire Core 30 and Breast Cancer-Specific Quality-of-Life Questionnaire), menopausal symptoms (Functional Assessment of Cancer Therapy-Breast endocrine symptom subscale), and anxiety and depression (Hopkins Symptom Checklist). RESULTS: In total, 107 women participated (adjuvant tamoxifen group, n = 20; surgical operation/radiotherapy group, n = 43; healthy control group, n = 44). Women in the adjuvant tamoxifen group had received tamoxifen for a mean (SD) of 31.5 (18.6) months (range, 15-79 mo) and performed worse on verbal memory than the surgical operation/radiotherapy group (P < 0.05) and the healthy control group (P < 0.05). Participants in the adjuvant tamoxifen group performed worse on measures of fluency than healthy controls (P < 0.05). Furthermore, women in the adjuvant tamoxifen group reported worse cognitive functioning (P < 0.05) than women in the surgical operation/radiotherapy group or the healthy control group. CONCLUSIONS: Our results provide insights into cognitive functioning in women who receive long-term adjuvant tamoxifen treatment. By adding the surgical operation/radiotherapy group, we could control for the mental and physical influences of the diagnosis and treatment of breast cancer. Cognitive domains that rely on verbal abilities (verbal memory and fluency) seem to be at risk for deterioration after treatment with tamoxifen.

Effects of low-frequency cranial electrostimulation on the rest-activity rhythm and salivary cortisol in Alzheimer's disease.

OBJECTIVE: In previous studies, cranial electrostimulation (CES) had positive effects on sleep in depressed patients and in patients with vascular dementia. The present study examined the effects of low-frequency CES on the rest-activity rhythm and cortisol levels of patients with probable Alzheimer's disease (AD). METHOD: It was hypothesised that a decreased level of cortisol would parallel a positive effect of low-frequency CES on nocturnal restlessness. Sixteen AD patients were randomly assigned to an experimental group (n = 8) or a control group (n = 8). The experimental group was treated with CES, whereas the control group received sham stimulation, for 30 minutes a day, during 6 weeks. The rest-activity rhythm was assessed by actigraphy. Cortisol was measured repeatedly in the saliva throughout the day by means of salivette tubes. RESULTS: Low-frequency CES did not improve the rest-activity rhythm in AD patients. Moreover, both groups showed an increase instead of a decrease in the level of cortisol. CONCLUSIONS: These preliminary results suggest that low-frequency CES has no positive effect on the rest-activity rhythm in AD patients. An alternative research design with high-frequency CES in AD is discussed.