Title: Neuropsychological Features in Primary Hyperparathyroidism ...

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We found no linear association between serum calcium or PTH and cognitive abnormalities. This may be because the study had limited power to evaluate this relationship or the range of serum calcium and PTH levels was too narrow to be able to discern the association. Studies in which the mean serum calcium values were much higher reported a relationship between preoperative neuropsychological symptoms and extent of hypercalcemia (19). Several studies from our group and others support the presence of increased vascular stiffness and endothelial dysfunction in PHPT (46-49). If present in the carotid or cerebral vasculature, vascular stiffness could represent a pathophysiological pathway leading to cognitive impairment. The study has several limitations. First, the PHPT and control groups differed with regard to two important parameters: estimated IQ and education level. The direction of the differences (PHPT subjects were better educated and with a higher estimated IQ), however, should have biased against our finding of worse cognitive function in the PHPT group. Although these differences were taken into account in the statistical analysis, adjustment may not fully account for these disparities. It is therefore possible, that if cases could have been ideally matched, the results may have differed. Although specific socioeconomic data were not available, the communities from which the samples were obtained are similar in this regard. We also suspect an association between socioeconomic level and education, for which we adjusted. There were also limitations inherent in the study design. An RCT of surgery versus no surgery is a superior design compared to a case-control study, but is extremely difficult to carry-out. Additionally, test administrators were not blinded to disease state and time of testing, which could have influenced results. Because we did not have a surgical control group, it is also possible that the pre-operative increase in symptoms of anxiety and depression could be explained by anticipation of surgery. Improvement in psychiatric symptoms may have been due to the knowledge of being free of disease or a non-specific effect of surgery rather than the correction of PHPT itself. However, if preoperative anxiety findings were related to impending surgery, an improvement would have been expected. Finally, we studied a convenience sample of PHPT patients including patients who did and did not meet 2002 criteria for surgery. The size of the cohort precludes a sub-group analysis (of those meeting versus those not meeting indications for surgery) to 12
address the issue of differing responses in these groups. However, it allowed us to achieve our main goal: to document the existence of cognitive symptoms among patients with mild PHPT. The clinical significance of the cognitive improvement after surgery is unclear, since the magnitude of changes was within one standard deviation of the group mean. It is notable, however, that the mean value for nonverbal abstraction, logic and problem solving was within 1 point of the mildly impaired range, a finding that was unexpected given participants’ high level of education. In addition, we do not know if these results apply to premenopausal women and men with PHPT. In spite of these limitations, the study has several notable strengths. We characterized cognitive function in a moderate sized group of patients with mild PHPT. Control data are available and a large battery of validated tests, which evaluated many aspects of cognition, was used. Patients and controls were studied at two identical time points, obviating confounding by learning effects known to exist in cognitive testing. Additionally, we studied patients well after the immediate post-operative period in order to prevent biases due to the non-specific benefits of surgery. Finally, we controlled for variables known to affect cognitive performance, including age, education and estimated IQ, and the presence of anxiety and depressive symptoms. We conclude that mild PHPT in postmenopausal women is associated with weaker performance in the cognitive domains of verbal memory and non-verbal abstraction. This is independent of anxiety and depressive symptoms, which are also more common in PHPT than in a control population. Parathyroidectomy leads to improvement in some of the psychiatric and cognitive deficits. While these results cannot be extrapolated to predict clinical expectations in any given patient, they may provide an explanation for the improved sense of well-being reported by many, but not all, patients after successful parathyroidectomy. Furthermore, these results may be useful in further research into specific neuroanatomical regions that may be specifically affected by the hyperparathyroid process. Acknowledgments 13
Page 1 and 2: J Clin Endocrin Metab. First publis
Page 3 and 4: Introduction Classical PHPT was a s
Page 5 and 6: malignancy other than non-melanoma
Page 7 and 8: 7. Non-verbal Abstraction: This was
Page 9 and 10: PHPT, mean performance levels on th
Page 11: RCT results have been inconsistent
Page 15 and 16: 14. Prager G, Kalaschek A, Kaczirek
Page 17 and 18: Figure legends Figure 1. A) Depress
Page 19 and 20: Table 2. Cognitive Testing Adjusted
Page 21 and 22: Figure 2 A. Wechsler Logical Memory
Page 23: Figure 4 Booklet Category Test T-sc

Title: Neuropsychological Features in Primary Hyperparathyroidism ...

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