Elsevier

Hormones and Behavior

Volume 59, Issue 4, April 2011, Pages 444-450
Hormones and Behavior

The relationship between IGF-I concentration, cognitive function and quality of life in adults with Prader–Willi syndrome

https://doi.org/10.1016/j.yhbeh.2011.01.001Get rights and content

Abstract

Mental retardation is one of the clinical characteristics of Prader–Willi syndrome (PWS) and in part of the patients growth hormone deficiency is demonstrable. Cognitive function seems to be influenced by insulin-like growth factor I (IGF-I); however, little is known about cognitive function in relation to IGF-I levels in PWS adults. The aim of the present study was to evaluate cognitive function in adult PWS patients in comparison to healthy siblings and to investigate whether there is a correlation between cognitive function and IGF-I levels. Anthropometric measurements, IGF-I levels, quality of life (QoL), Appetite Assessment Score, IQ (GIT and Raven) and cognitive function (by four subtests of the Cambridge Neuropsychological Automated Testing Battery, CANTAB) were evaluated in PWS patients and their healthy siblings served as control group. PWS patients had significantly lower IGF-I levels, IQ and QoL when compared to controls. Reaction times were longer and performance was worse on CANTAB subtests in PWS adults. IGF-I on one hand and IQ, Appetite Assessment Score and cognitive performance on the other hand seem to be correlated in PWS patients. In conclusion, IGF-I levels, IQ and QoL are significantly lower in PWS subjects when compared to healthy siblings. In PWS adults, temporal as well as prefrontal cognitive functions are impaired. Higher IGF-I levels appear to be related to better intellectual skills and faster temporal memory processing in PWS patients.

Research highlights

►Insulin-like growth factor I level decreased in adults with Prader–Willi syndrome. ►Worse temporal and prefrontal functions in adults with Prader–Willi syndrome. ►Insulin-like growth factor I level related to intellectual skills. ►Insulin-like growth factor I level related to temporal memory processing.

Introduction

The Prader–Willi syndrome (PWS) was described by the Swiss physicians Prader, Labhart and Willi in 1956 (Prader et al., 1956). PWS is clinically characterized by hyperphagia, morbid obesity, hypogonadism, hypotonia, behavioral abnormalities, short stature and mental retardation (Prader et al., 1956, Holm et al., 1993, Cassidy, 1997, Goldstone et al., 2008, Cassidy and Driscoll, 2009). In the past the diagnosis of Prader–Willi syndrome was made upon specific diagnostic criteria as published by Holm et al. (1993). Nowadays, PWS can be genetically confirmed. In about 60–75% of the affected individuals a paternally derived deletion of the 15q11-q13 region can be demonstrated (Ledbetter et al., 1981) and in about 20–30% of the cases there is a maternal uniparental disomy (mUPD) of chromosome 15 (Nicholls et al., 1989). Translocations and imprinting defects account for 1–5% of the cases (Buiting et al., 1995).

Studies on cognitive performance in PWS subjects show mild to moderate mental retardation with a mean full-scale intelligence quotient (IQ) between 50 and 70, with scores ranging from 35 to 100 in some studies, but in other studies a normal to borderline full-scale IQ score is described (Waters et al., 1990, Curfs et al., 1991, Roof et al., 2000, Gross-Tsur et al., 2001, Whittington et al., 2004a, Whittington et al., 2004b, Hoybye et al., 2005). Patterns of intellectual strengths and weaknesses have been examined, but results are not consistent. A significantly higher verbal IQ score in PWS subjects with a mUPD when compared to subjects with a paternal deletion has been described (Roof et al., 2000). Strengths in tasks as reading and vocabulary and weaknesses in tasks that involve sequential information processing using the auditory modality have also been reported (Gabel et al., 1986, Curfs et al., 1991, Dykens et al., 1992). In contrast to a relatively high full-scale IQ score in some PWS subjects, their performance on social, behavioral and neuropsychological abilities is lower than predicted by their IQ scores (Gross-Tsur et al., 2001, Whittington et al., 2004a).

Structural MRI scans of the brain have revealed white matter lesions in PWS subjects in cortical, subcortical and periventricular regions. Decreased brain volume in the parietal–occipital lobe, ventriculomegaly, Sylvian fissure abnormalities and lack of complete insula closure have also been described (Miller et al., 2006). Furthermore, subjects with PWS were found to exhibit mild frontal cortical atrophy, delayed myelination, a small brainstem and slight ventriculomegaly (Hashimoto et al., 1998).

PWS patients are characterized by (severe) obesity in the majority of the cases. Muscle mass and lean body mass are decreased. Fat mass is increased in both obese and non-obese subjects with PWS when compared to subjects with simple obesity and a corresponding BMI (Brambilla et al., 1997, Davies, 1999, Burman et al., 2001, Goldstone et al., 2001, Goldstone et al., 2002, Hoybye, 2004). The abnormal body composition as described in PWS exhibits similarity with the body composition changes found in growth hormone deficient (GHD) individuals (Brambilla et al., 1997, Davies, 1999, Goldstone et al., 2001). Growing evidence is available now that GHD independent of the obese state is demonstrable in both children and adults with PWS. Low levels of free insulin-like growth factor I (IGF-I) are described in both obese and non-obese PWS subjects in combination with decreased GH secretion after pharmacological stimulation (Corrias et al., 2000, Grugni et al., 2006).

Obesity is related to lower IQ in healthy subjects (Olsson and Hulting, 2010). Serum IGF-I levels in healthy elderly subjects correlate positively with cognitive functioning (Arwert et al., 2005). Furthermore, there are indications that quality of life (QoL) as well as cognitive functioning, particularly attention and memory, are impaired in adults with GHD (Deijen and Arwert, 2006, van Nieuwpoort and Drent, 2008). An impaired QoL has also been described in PWS patients (Caliandro et al., 2007).

The aim of the present study was to evaluate cognitive function and QoL in a sample of adult patients with PWS in comparison to their healthy siblings. Furthermore, we aimed to investigate whether there is a correlation between cognitive functioning and QoL on the one hand and serum IGF-I levels on the other hand. As a consequence of abnormal brain development due to genetic factors we expected subjects with PWS to be cognitively impaired relative to healthy controls. Our hypothesis was that this cognitive impairment in PWS subjects, as a consequence of low IGF-I levels, would be most noticeable with respect to temporal and prefrontal functions. In line with this assumption, we expected to find a positive relationship between IGF-I levels and cognitive performance within the PWS group. Finally, we investigated differences in QoL between PWS subjects and their healthy siblings, hypothesizing that a lower QoL would be present in the PWS group.

Section snippets

Patients

Subjects for this study were recruited via the Dutch Prader–Willi patients’ association. We included 15 PWS patients with genetically confirmed PWS. All patients were Caucasian. Median age of the PWS patients (4 males and 11 females) was 22.0 years (range 19.2–42.9 years). Four patients were treated with growth hormone in the past, but all stopped treatment at least 5 months before this study. Two of the patients suffered from hypothyroidism and were using thyroxine in a stable dose. In one of

Results

Table 1 shows the baseline characteristics of the PWS patients and the control subjects. Outcomes of tests of cognitive functioning, QoL and the 10-point Likert Scale Appetite Assessment Score are presented in Table 2. There were no significant differences between males and females with respect to any of the physical or psychological parameters, except for percent fat mass (p = 0.048). In addition, the distribution of sex was not significantly different across experimental groups. Therefore,

Discussion

The present study was aimed to elucidate cognitive impairments in PWS subjects. Particularly, the relationship between cognitive functions and IGF-I levels was examined. As a consequence of global brain damage PWS patients were hypothesised to be cognitively impaired in a variety of cognitive functions. In addition, most distinctive impairments were expected in temporal and prefrontal functions as a result of subnormal IGF-I levels.

First of all, low IGF-I levels were indeed observed in PWS

Conflict of interest

The authors declare no conflict of interest

Acknowledgments

We are very grateful to the Dutch Prader–Willi patients’ association for their help to recruit participants for this study. We would also like to thank all PWS patients, their brothers and sisters and the parents/caretakers of the PWS patients for participating in this study. This study was partly funded by an independent grant from Pfizer Inc.-Netherlands.

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