INTRODUCTION
Pituitary adenomas, even after successful treatment, are associated with cognitive dysfunctions (Peace et al., Reference Peace, Orme, Thompson, Padayatty, Ellis and Belchetz1997). Impairments in memory and executive function have been reported by several studies (Grattan-Smith, Morris, Shores, Batchelor, & Sparks, Reference Grattan-Smith, Morris, Shores, Batchelor and Sparks1992; Guinan, Lowy, Stanhope, Lewis, & Kopelman, Reference Guinan, Lowy, Stanhope, Lewis and Kopelman1998; Peace et al., Reference Peace, Orme, Thompson, Padayatty, Ellis and Belchetz1997; Peace, Orme, Padayatty, Godfrey, & Belchetz, Reference Peace, Orme, Padayatty, Godfrey and Belchetz1998). Many factors might contribute to these cognitive problems in patients diagnosed with and treated for pituitary adenoma, including mass effects from the original tumor on structures adjacent to the pituitary and hormonal imbalances. In light of the more severe impairments in surgically treated patients, the surgical procedure may be an additional contributing factor (Guinan et al., Reference Guinan, Lowy, Stanhope, Lewis and Kopelman1998; Peace et al., Reference Peace, Orme, Thompson, Padayatty, Ellis and Belchetz1997, Reference Peace, Orme, Padayatty, Godfrey and Belchetz1998). Although radiotherapy does not appear to impair cognitive function in patients treated for pituitary adenoma (Guinan et al., Reference Guinan, Lowy, Stanhope, Lewis and Kopelman1998; Peace et al., Reference Peace, Orme, Thompson, Padayatty, Ellis and Belchetz1997, Reference Peace, Orme, Padayatty, Godfrey and Belchetz1998), the impact of the kind of surgical route (transsphenoidal vs. transfrontal) is controversial in the literature. Peace et al. (Reference Peace, Orme, Padayatty, Godfrey and Belchetz1998) found more severe impairment after transfrontal than after transsphenoidal surgery, whereas Guinan et al. (Reference Guinan, Lowy, Stanhope, Lewis and Kopelman1998) did not find an association between treatment invasiveness and the degree of cognitive impairment.
Several previous studies have shown that neuropsychological recovery after traumatic brain injury in adults was favorably moderated by younger age (Green et al., Reference Green, Colella, Christensen, Johns, Frasca, Bayley and Monette2008; Testa et al., Reference Testa, Malec, Moessner and Brown2005; Willemse-van Son, Ribbers, Verhagen, & Stam, Reference Willemse-van Son, Ribbers, Verhagen and Stam2007; Wilson, Reference Wilson1998). Given that the influence of age at definitive treatment on cognitive function has, so far, not been investigated in patients surgically treated for pituitary adenoma, we aimed to test this association in the present study. We hypothesized that younger age at the time of treatment is associated with better neuropsychological outcome after successful intervention for pituitary adenoma.
METHODS
Participants
Participants were recruited from the endocrine outpatient clinics of the University Hospital of Tübingen. Inclusion criteria were successful definitive treatment for pituitary adenoma (pituitary surgery with or without subsequent radiotherapy), with no evidence of biochemical excess of growth hormone (GH), adrenocorticotrophic hormone (ACTH), prolactin, thyroid-stimulating hormone (TSH), or gonadotropins, and appropriate doses of hormone replacement as measured by endocrine tests on the day of neuropsychological testing. The length of time post-surgery ranged from 4 to 31 years [mean = 14 years, standard deviation (SD) = 8 years]. Thyroid, glucocorticoid, sex steroid, and growth hormone replacement therapies were considered adequate if free thyroxine (fT4) and free tri-iodothyronine (fT3) plasma levels were within the normal range, if the patient was receiving between 20 and 30 mg of hydrocortisone or between 25 and 37.5 mg of cortisone acetate per day, if plasma levels of testosterone or estradiol, respectively, were within the normal range, and if insulin-like growth factor-1 (IGF-1) levels were within the age-related normal range. Exclusion criteria comprised psychiatric and neurological disorders, major comorbidities known to affect neurocognitive function, such as liver abnormalities (alkaline phosphate, aspartate amino transferase, alanine amino transferase, or gamma glutamyl transferase levels 2 or more times the upper reference range), chronic renal failure (serum creatinine >1.5 mg/dl), marked anemia (Hb < 8.0 mg/dl), history of thyroid cancer requiring suppression of TSH secretion, visual deficits (an impairment in vision that, even with correction, adversely affects educational performance; i.e., a visual acuity of 20/70 or less in the better eye with best correction, or a visual field of 140 degrees or less in the better eye), and thyroid autoimmune diseases. The local ethics committee approved the protocol (protocol number: 249/2006V). Informed written consent was obtained from all participants.
Laboratory Methods for Hormone Concentrations
Cortisone-binding globulin (CBG), cortisol, estradiol, follicle-stimulating hormone (FSH), fT3, fT4, luteinizing hormone (LH), testosterone, and TSH were measured by an immunometric assay on the ADVIA Centaur analyser (Siemens Medical Solutions Diagnostics, Los Angeles, CA). ACTH, GH, insulin-like growth factor-1 (IGF-1), and sex hormone-binding globulin (SHBG) were measured by an immunometric assay on the Immulite 2500 analyzer (Siemens Medical Solutions Diagnostics, Los Angeles, CA).
Neuropsychological Testing
Established and validated neuropsychological tests were utilized. Executive function was examined with the Trail –Making Test (TMT), which requires a subject to connect-the-dots of 25 consecutive targets on a sheet of paper. Two versions are available: A, in which the targets are all numbers (1, 2, 3, etc.), and B, in which the subject alternates between numbers and letters (1, A, 2, B, etc.). TMT-A examines attentional speed, and TMT-B is a measure of executive control and attention (Reitan, Reference Reitan1992).
Verbal memory was assessed with the German version of the Auditory Verbal Learning and Memory Test (VLMT), which consists of five presentations with recall of a 15-word list, one presentation of a second 15-word list (interference test), a sixth recall trial of the first word list, and a delayed recognition test after 30 min (Helmstaedter, Lendt, & Lux, Reference Helmstaedter, Lendt and Lux2001).
Acoustic working memory was assessed with the digit span test of the German version of the Wechsler Adult Intelligence Scale (WAIS) in which a subject is read a list of numbers and then asked to repeat it both forward and backward (Tewes, Reference Tewes1999).
Premorbid intelligence was estimated based on post-surgery administration of the Multiple Choice Word Fluency Test (MWT-B). It consists of 37 items requesting the individual to select the only meaningful term from among five options given for each item (Lehrl, Reference Lehrl2005).
Below average performance was defined as a score above 39 s for TMT-A, above 85 s for TMT-B (Reitan, Reference Reitan1992), below 40 for VLMT (T-scores; Helmstaedter et al., Reference Helmstaedter, Lendt and Lux2001), and below 7 for the digit span test (age-related scores; Tewes, Reference Tewes1999).
Data Analysis
Ln-transformation of nonnormally distributed parameters was performed prior to statistical analysis. Distribution was tested for normality using the Shapiro-Wilk W test. To identify potential confounding variables, stepwise regression analysis was performed using a backward elimination approach. In multivariate linear regression analyses, neurocognitive performance was the dependent variable, whereas age at treatment, age at testing, and time since treatment were the independent variables. A p value <.05 was considered statistically significant. The statistical software package JMP 7.0 (SAS Institute, Cary, NC) was used.
RESULTS
Forty-two patients (17 males, 25 females) participated in this study. At the time of testing, the age of the patients ranged from 28 to 65 years (mean = 51 years, SD = 10 years). The age range at definitive treatment was 17 to 57 years (mean = 37 years, SD = 11 years). Participants had undergone transsphenoidal surgery for nonfunctioning adenoma in 6 cases, for prolactinoma in 11 cases, for acromegaly in 14 cases, and for Cushing’s disease in 11 cases. The range of tumor size was 2 to 55 mm (mean = 17 mm, SD = 13 mm). In 12 participants, cure required two or more interventions, with 4 patients receiving a transfrontal approach. Radiotherapy was carried out in 18 cases.
All pituitary patients had normal estimated premorbid intelligence (IQ: mean = 106, SD = 13), as assessed by the MWT-B test. The pituitary adenoma group displayed attention and executive functioning deficits, as assessed by increased mean values of the TMT-A (mean = 42 s, SD = 19 s) and TMT-B (mean = 98 s, SD = 51 s) tests. Approximately half of the subjects showed results below the average in both tests. Although mean values of the VLMT (T-score: T1, mean = 49, SD = 9; T2, mean = 46, SD = 9; T3, mean = 45, SD = 9; T4, mean = 46, SD = 9) and digit span test (age-related score: mean = 11, SD = 3) were within the normal range, in the VLMT subtests, which assess verbal memory, up to one third of patients showed results below the average range.
We found a highly significant association between age at definitive treatment and results in TMT-B (r = .60, p < .0001). Participants diagnosed at a younger age showed better performance. Previous studies reported correlations among TMT performance with age, education, and gender (Drane, Yuspeh, Huthwaite, & Klingler, Reference Drane, Yuspeh, Huthwaite and Klingler2002; Heaton, Avitable, Grant, & Matthews, Reference Heaton, Avitable, Grant and Matthews1999). To identify potential confounding variables in our study, we performed a stepwise regression analysis, comprising age, gender, and education level, as well as other clinical factors, such as surgical route (transsphenoidal vs. transfrontal), number of surgeries, radiotherapy, tumor size, and time since treatment, which may influence neurocognitive function. The analysis showed that only age at testing and time since treatment independently contributed to predict TMT-B performance (p = .0012 and p < .0001, respectively), whereas the other factors did not influence results in TMT-B (all p ≥ .13). Also after adjustment for age at testing and time since treatment, the association between age at definitive treatment and results in TMT-B remained significant (r = .42, p = .008; Figure 1a). In contrast, no associations were detected between age at definitive treatment and TMT-A, digit span test, and VLMT (all p ≥ .3).
Association of age at definitive treatment with executive function as assessed by (a) TMT-B scores and (b) TMT-B-A scores after successful surgery for pituitary adenoma. As TMT-B scores reflect not only executive function but also attention, we computed TMT-B-A scores by subtracting TMT-A scores (indicating attentional speed) from TMT-B scores (indicating the more executive aspect of divided attention). For statistical analysis, the data were ln-transformed and adjusted for age at testing and time since treatment. Sec = seconds; TMT = Trail –Making Test; yr = years.
Since TMT-B scores reflect not only executive function but also attention, we computed TMT-B-A scores by subtracting TMT-A scores (indicating attentional speed) from TMT-B scores (indicating the more executive aspect of divided attention). In a multiple regression analysis, age at definitive treatment was associated with TMT-B-A, which represents in contrast to TMT-B executive functioning only, when controlling for the influence of age at testing and time since treatment (r = .32, p = .04; Figure 1b).
DISCUSSION
In accordance with previous studies (Guinan et al., Reference Guinan, Lowy, Stanhope, Lewis and Kopelman1998; Peace et al., Reference Peace, Orme, Thompson, Padayatty, Ellis and Belchetz1997, Reference Peace, Orme, Padayatty, Godfrey and Belchetz1998), we detected deficits in memory and executive function in patients treated surgically for pituitary adenoma. Moreover, our data show that executive function was significantly associated with age at treatment, and that younger patients at definitive treatment exhibited a better outcome. This association remained significant after adjustment for the confounding variables age at testing and time since treatment and was independent of surgical route (transsphenoidal vs. transfrontal), the number of surgeries, radiotherapy, and tumor size.
Our results are in agreement with previous studies in adults indicating that a younger age at the time of insult is a favorable recovery factor after brain injury (Green et al., Reference Green, Colella, Christensen, Johns, Frasca, Bayley and Monette2008; Testa et al., Reference Testa, Malec, Moessner and Brown2005; Willemse-van Son et al., Reference Willemse-van Son, Ribbers, Verhagen and Stam2007; Wilson, Reference Wilson1998). The reasons for the favorable effect of younger age in adults on neurocognitive outcome after traumatic brain injuries in previous studies and after surgery for pituitary adenoma in our study could be explained by two mechanisms.
The adult central nervous system possesses the life-long capacity for physical and functional changes enabling an effective cognitive rehabilitation after acquired brain injury. However, this neural plasticity declines with age (Burke & Barnes, Reference Burke and Barnes2006). Therefore, the decrease of neuroplasticity with age may be an explanation for the better outcome of cognitive functions following nonprogressive brain injury in younger adults. This assumption, however, is not supported by all studies (Reeder, Rosenthal, Lichtenberg, & Wood, Reference Reeder, Rosenthal, Lichtenberg and Wood1996).
An alternative explanation for our finding may be the special vulnerability of elderly patients to neurologic disease and injury (Kulchycki & Edlow, Reference Kulchycki and Edlow2006). In particular, the prefrontal cortex, the key brain area involved in executive function, shows considerable age-related neuronal loss and decline in white matter integrity (Burke & Barnes, Reference Burke and Barnes2006). The recuperative effects of younger age may, therefore, be attributable to greater reserve capacity of these brain areas.
The underlying mechanisms leading to an age-related decline of ability to recover from brain injury comprise a variety of factors, including region-specific changes in dendritic morphology, cellular connectivity, calcium dysregulation, gene expression, or other factors that alter neural network dynamics (Burke & Barnes, Reference Burke and Barnes2006). Furthermore, a growing body of evidence suggests that the GH/IGF-1 axis, which declines in parallel with cognitive function during aging, is involved in neuroprotection, regeneration, and functional plasticity in the adult brain (Sonntag, Ramsey, & Carter, Reference Sonntag, Ramsey and Carter2005).
It is worth noting that we did not find an association between memory function and age at treatment. The reasons for the different influences of pituitary surgery on neurocognitive functions are not clear, and should be elucidated in future studies.
In conclusion, to the best of our knowledge, this is the first study reporting an association between age at surgery and executive function after successful treatment in patients with pituitary adenoma, with younger patients showing a better outcome. In future studies the underlying mechanisms should be carefully investigated.
ACKNOWLEDGMENT
The authors thank Mary-Ann Schneider for proofreading the manuscript. The authors declare that there is no conflict of interest.
