Martin F. Elderson

Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy

Context and objective  Cognitive deterioration is reported in patients with a nonfunctioning pituitary macroadenoma (NFA) and after pituitary radiotherapy. However, reported results are inconsistent and are potentially confounded by different underlying pituitary disorders. The aim of this study was to examine cognitive functions in patients previously treated for NFA with or without radiotherapy.

Cognitive performance after postoperative pituitary radiotherapy: a dosimetric study of the hippocampus and the prefrontal cortex

OBJECTIVE The hippocampus and prefrontal cortex (PFC) are important for memory and executive functioning and are known to be sensitive to radiotherapy (RT). Radiation dosimetry relates radiation exposure to specific brain areas. The effects of various pituitary RT techniques were studied by relating detailed dosimetry of the hippocampus and PFC to cognitive performance. METHODS In this cross-sectional design, 75 non-functioning pituitary macroadenoma (NFA) patients (61±10 years) participated and were divided into irradiated (RT+, n=30) and non-irradiated (RT-, n=45) groups. The RT+ group (who all received 25 fractions of 1.8 Gy; total dose: 45 Gy) consisted of three RT technique groups: three-field technique, n=10; four-field technique, n=15; and five-field technique, n=5. Memory and executive functioning were assessed by standardized neuropsychological tests. A reconstruction of the dose distributions for the three RT techniques was made. The RT doses on 30, 50, and 70% of the volume of the left and right hippocampus and PFC were calculated. RESULTS Cognitive test performance was not different between the four groups, despite differences in radiation doses applied to the hippocampi and PFC. Age at RT, time since RT, and the use of thyroid hormone varied significantly between the groups; however, they were not related to cognitive performance. CONCLUSION This study showed that there were no significant differences on cognitive performance between the three-, four-, and five-field RT groups and the non-irradiated patient group. A dose-response relationship could not be established, even with a radiation dose that was higher on most of the volume of the hippocampus and PFC in case of a four-field RT technique compared with the three- and five-field RT techniques.

No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study

INTRODUCTION The presence of the Thr92Ala polymorphism of deiodinase-2 (D2) has been thought to have several effects. It may influence its enzymatic function, is associated with increased expression of genes involved in oxidative stress in brain tissue, and may predict favorable response to combination levothyroxine (LT4) plus triiodothyronine (T3) therapy. It was hypothesized that homozygous carriers of the D2-92Ala allele have different thyroid hormone parameters, and reduced health-related quality of life (HRQoL) and cognitive functioning. METHODS In 12,625 participants from the LifeLines cohort study with genome-wide genetic data available, the effects of the Thr92Ala polymorphism (rs225014) were evaluated in the general population and in 364 people treated with thyroid hormone replacement therapy, the latter mainly because of primary hypothyroidism. In addition to evaluating anthropometric data, medication use, and existence of metabolic syndrome, HRQoL was assessed with the RAND 36-Item Health Survey, and the Ruff Figural Fluency Test was used as a sensitive test for executive functioning. Data on thyrotropin, free thyroxine (fT4), and free T3 (fT3) levels were available in a subset of 4479 participants. RESULTS The mean age (±standard deviation) was 53 ± 12 years and the body mass index was 27.0 ± 4.5 kg/m2 in the LT4 users compared with 48 ± 11 years and 26.2 ± 4.1 kg/m2 in participants from the general population. The Ala/Ala genotype of the D2-Thr92Ala polymorphism was present in 11.3% of LT4 users and in 10.7% of the general population. In total, 3742/4479 subjects with thyroid hormone data available had normal TSH (0.4-4.0 mIU/L), and 88% of LT4 users were females. LT4 users had higher fT4, lower fT3, and a lower fT3/fT4 ratio, and female patients had lower scores on the HRQoL domains of physical functioning, vitality, mental health, social functioning, bodily pain, and general health compared with those not using LT4 (p < 0.005). Executive functioning scores, as part of cognitive functioning, were comparable between female LT4 users and the general population. In both groups, the D2-Thr92Ala polymorphism was not associated with differences in TSH, fT4, fT3, the fT3/fT4 ratio, presence of metabolic syndrome or other comorbidities, use of medication, HRQoL, and cognitive functioning. CONCLUSION The Thr92Ala polymorphism of D2 was not associated with thyroid parameters, HRQoL, and cognitive functioning in the general population and in participants on thyroid hormone replacement therapy.

Cognition and brain abnormalities on MRI in pituitary patients

PURPOSE The extent to which cognitive dysfunction is related to specific brain abnormalities in patients treated for pituitary macroadenoma is unclear. Therefore, we compared brain abnormalities seen on Magnetic Resonance Imaging (MRI) in patients treated for nonfunctioning pituitary macroadenoma (NFA) with or without impairments in cognitive functioning. METHODS In this cross-sectional design, a cohort of 43 NFA patients was studied at the University Medical Center Groningen. White matter lesions (WMLs), cerebral atrophy, (silent) brain infarcts and abnormalities of the temporal lobes and hippocampi were assessed on pre-treatment and post-treatment MRI scans. Post-treatment cognitive examinations were performed using a verbal memory and executive functioning test. We compared our patient cohort with large reference populations representative of the Dutch population. RESULTS One or more impairments on both cognitive tests were frequently observed in treated NFA patients. No treatment effects were found with regard to the comparison between patients with and without impairments in executive functioning. Interestingly, in patients with one or more impairments on verbal memory function, treatment with radiotherapy had been given more frequently (74% in the impaired group versus 40% in the unimpaired group, P=0.025). Patients with or without any brain abnormality on MRI did not differ in verbal memory or executive functioning. CONCLUSIONS Brain abnormalities on MRI are not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning. Conversely, the absence of brain abnormalities on MRI does not exclude impairments in cognition.

Agreement between Computerized and Human Assessment of Performance on the Ruff Figural Fluency Test

The Ruff Figural Fluency Test (RFFT) is a sensitive test for nonverbal fluency suitable for all age groups. However, assessment of performance on the RFFT is time-consuming and may be affected by interrater differences. Therefore, we developed computer software specifically designed to analyze performance on the RFFT by automated pattern recognition. The aim of this study was to compare assessment by the new software with conventional assessment by human raters. The software was developed using data from the Lifelines Cohort Study and validated in an independent cohort of the Prevention of Renal and Vascular End Stage Disease (PREVEND) study. The total study population included 1,761 persons: 54% men; mean age (SD), 58 (10) years. All RFFT protocols were assessed by the new software and two independent human raters (criterion standard). The mean number of unique designs (SD) was 81 (29) and the median number of perseverative errors (interquartile range) was 9 (4 to 16). The intraclass correlation coefficient (ICC) between the computerized and human assessment was 0.994 (95%CI, 0.988 to 0.996; p<0.001) and 0.991 (95%CI, 0.990 to 0.991; p<0.001) for the number of unique designs and perseverative errors, respectively. The mean difference (SD) between the computerized and human assessment was -1.42 (2.78) and +0.02 (1.94) points for the number of unique designs and perseverative errors, respectively. This was comparable to the agreement between two independent human assessments: ICC, 0.995 (0.994 to 0.995; p<0.001) and 0.985 (0.982 to 0.988; p<0.001), and mean difference (SD), -0.44 (2.98) and +0.56 (2.36) points for the number of unique designs and perseverative errors, respectively. We conclude that the agreement between the computerized and human assessment was very high and comparable to the agreement between two independent human assessments. Therefore, the software is an accurate tool for the assessment of performance on the RFFT.

Cognitief functioneren bij patiënten die behandeld zijn voor een niet functionerende hypofysemacro-adenoom en de effecten van hypofysebestraling

Niet functionerende hypofysemacro-adenomen (NFA) zijn goedaardige tumoren van de hypofyse die door druk op de oogzenuwen uitval van het gezichtvermogen kunnen geven en tevens kunnen leiden tot verlies van de hypofysefunctie. De aanbevolen behandeling bestaat uit transsfenoïdale chirurgie soms gevolgd door radiotherapie indien er sprake is van een tumorrest of hergroei. De lokale tumorcontrole verbetert sterk door de toepassing van radiotherapie op de hypofyse (Van den Bergh et al., 2007). Naast deze positieve effecten op tumorcontrole, worden er cognitieve veranderingen gevonden in het geheugen en executieve functies (o.a. planning, cognitieve flexibiliteit en inhibitie) bij behandelde hypofysepatiënten (Guinan et L., 1998; Noad et al., 2004; Peace et al., 1997; Peace et al., 1998). Eerdere studies hadden echter als nadeel dat de patiëntenpopulaties heterogeen waren ten aanzien van de hypofyse aandoening en bovendien vaak klein waren.