Skip to main content

White matter involvement on DTI-MRI in Cushing’s syndrome relates to mood disturbances and processing speed: a case-control study

Abstract

Purpose

Cushing’s syndrome (CS) is an endocrine disorder due to prolonged exposure to cortisol. Recently, microstructural white matter (WM) alterations detected by diffusion tensor imaging (DTI) have been reported in CS patients, and related to depression, but other functional significances. remain otherwise unclear. We aimed at investigating in more depth mood symptoms in CS patients, and how these relate to cognition (information processing speed), and to WM alterations on DTI.

Methods

The sample comprised 35 CS patients and 35 healthy controls. Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, State-Trait Anxiety Inventory (STAI) to assess anxiety, and processing speed was measured by the Symbol Digit Modalities Test (SDMT). DTI studies were acquired using a 3-Tesla Philips-Achieva MR-facility. Voxelwise statistical analysis of fractional anisotropy (FA), mean, axial and radial diffusivities (MD, AD, RD) data were performed using FMRIB Software Library. Correlation analysis were obtained between mood and processing speed variables, and FA, MD, AD and RD values, taking both CS patients and healthy controls.

Results

Active, controlled and cured CS patients showed greater depression (F = 12.4, p < 0.001), anxious state (F = 4.8, p = 0.005) and anxious trait (F = 9.6, p < 0.001) scores, than controls. Using the entire sample, depression scores correlated negatively to FA and positively to RD values. Although there were no differences in processing speed between groups, SDMT scores correlated positively to both FA and AD values.

Conclusions

There were greater depressive and anxious symptoms in CS patients than in healthy controls, but no difference in processing speed. However, DTI is related to depression and information processing speed in CS.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Bertagna X, Guignat L, Groussin L, Bertherat J (2009) Cushing’s disease. Best Pract Res Clin Endocrinol Metab 23(5):607–623

    CAS  Article  PubMed  Google Scholar 

  2. Hatipoglu BA (2012) Cushing’s syndrome. J Surg Oncol 106(5):565–571

    CAS  Article  PubMed  Google Scholar 

  3. Starr AM (1952) Personality changes in Cushing’s syndrome. J Clin Endocrinol Metab 12(5):502–505

    CAS  Article  PubMed  Google Scholar 

  4. Kelly WF (1996) Psychiatric aspects of Cushing’s syndrome. QJM 89(7):543–551

    CAS  Article  PubMed  Google Scholar 

  5. Loosen PT, Chambliss B, DeBold CR, Shelton R, Orth DN (1992) Psychiatric phenomenology in Cushing’s disease. Pharmacopsychiatry 25(4):192–198

    CAS  Article  PubMed  Google Scholar 

  6. Bourdeau I, Bard C, Forget H, Boulanger Y, Cohen H, Lacroix A (2005) Cognitive function and cerebral assessment in patients who have Cushing’s syndrome. Endocrinol metab clin N Am 34(2), 357–369

    CAS  Article  Google Scholar 

  7. Andela CD, Van Haalen F, Ragnarsson O, Papakokkinou E, Johannsson G, Santos A, Webb S, Biermasz NR, van der Wee NJ, Pereira AM (2015) Mechanisms in endocrinology: Cushing’s syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies. Eur J Endocrinol 173(1):R1–R14

    CAS  Article  PubMed  Google Scholar 

  8. Budde MD, Xie M, Cross AH, Song SK (2009) Axial diffusivity is the primary correlate of axonal injury in the experimental autoimmune encephalomyelitis spinal cord: a quantitative pixelwise analysis. J Neurosci 29(9):2805–2813. doi:10.1523/JNEUROSCI.4605-08.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Alexander AL, Lee JE, Lazar M, Field AS (2007) Diffusion tensor imaging of the brain. Neurotherapeutics 4(3):316–329. doi:10.1016/j.nurt.2007.05.011

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pires P, Santos A, Vives-Gilabert Y, Webb SM, Sainz-Ruiz A, Resmini E, Crespo I, de Juan-Delago M, Gómez-Anson B (2015) White matter alterations in the brains of patients with active, remitted, and cured cushing syndrome: a DTI study. AJNR Am J Neuroradiol 36(6):1043–1048

    CAS  Article  PubMed  Google Scholar 

  11. van der Werff SJA, Andela CD, Nienke Pannekoek J, Meijer OC, van Buchem MA, Rombouts SARB, van der Mast RC, Biermasz NR, Pereira AM, van der Wee NJA (2014) Widespread reductions of white matter integrity in patients with long-term remission of Cushing’s disease. NeuroImage 4, 659–667. doi:10.1016/j.nicl.2014.01.017

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gutiérrez R, Boison D, Heinemann U, Stoffel W (1995) Decompaction of CNS myelin leads to a reduction of the conduction velocity of action potentials in optic nerve. Neurosci Lett 195(2):93–96

    Article  PubMed  Google Scholar 

  13. Hsu JL, Chen YL, Leu JG, Jaw FS, Lee CH, Tsai YF, Hsu CY, Bai CH, Leemans A (2012) Microstructural white matter abnormalities in type 2 diabetes mellitus: a diffusion tensor imaging study. Neuroimage 59(2):1098–1105. doi:10.1016/j.neuroimage.2011.09.041

    Article  PubMed  Google Scholar 

  14. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571

    CAS  Article  PubMed  Google Scholar 

  15. Smith A (1982) Symbol digit modalities test: manual. Western Psychological Services, Los Angeles

    Google Scholar 

  16. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23(Suppl 1):S208–219. doi:10.1016/j.neuroimage.2004.07.051

    Article  PubMed  Google Scholar 

  17. https://neuroweb.pic.es

  18. Smith SM (2002) Fast robust automated brain extraction. Hum Brain Mapp 17(3):143–155. doi:10.1002/hbm.10062

    Article  PubMed  Google Scholar 

  19. Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE (2006) Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487–1505

    Article  PubMed  Google Scholar 

  20. Smith SM, Nichols TE (2009) Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage, 44(1), 83–98. doi:10.1016/j.neuroimage.2008.03.061

    Article  PubMed  Google Scholar 

  21. Sonino N (1997) From the lesson of Harvey Cushing to current knowledge: psychosocial aspects of endocrine disease. Psychother Psychosom 66:113–116

    CAS  Article  PubMed  Google Scholar 

  22. Sonino N, Fava GA (2001) Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs 15:361–373

    CAS  Article  PubMed  Google Scholar 

  23. Sonino N, Fallo F, Fava GA (2010) Psychosomatic aspects of Cushing’s syndrome. Rev Endocr Metab Disord 11(2):95–104. doi:10.1007/s11154-009-9123-7

    Article  PubMed  Google Scholar 

  24. Starkman MN, Schteingart DE, Schork MA (1981) Depressed mood and other psychiatric manifestations of Cushing’s syndrome: relationship to hormone levels. Psychosom Med 43(1):3–18

    CAS  Article  PubMed  Google Scholar 

  25. Kelly WF, Kelly MJ, Faragher B (1996) A prospective study of psychiatric and psychological aspects of Cushing’s syndrome. Clin Endocrinol 45(6):715–720

    CAS  Article  Google Scholar 

  26. Andela CD, Van Haalen F, Ragnarsson O, Papakokkinou E, Johannsson G, Santos A, Webb S, Biermasz NR, van der Wee NJ, Pereira AM (2015) Mechanisms in endocrinology: Cushing’s syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies. Eur J Endocrinol 173(1):R1–R14. doi:10.1530/EJE-14-1101

    CAS  Article  PubMed  Google Scholar 

  27. Sonino N, Navarrini C, Ruini C, Ottolini F, Paoletta A, Fallo F, Boscaro M, Fava GA (2004) Persistent psychological distress in patients treated for endocrine disease. Psychother Psychosom, 73(2):78–83. doi:10.1159/000075538

    Article  PubMed  Google Scholar 

  28. Sobrinho LG (2004) Psychopathology in endocrine disorders: why so persistent after the cure? Psychother Psychosom 73(2):65–67. doi:10.1159/000075536

    Article  PubMed  Google Scholar 

  29. Pereira, AM, Tiemensma J, Romijn JA (2010) Neuropsychiatric disorders in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1):65–70. doi:10.1159/000314317

    CAS  Article  PubMed  Google Scholar 

  30. Heald AH, Ghosh S, Bray S, Gibson C, Anderson SG, Buckler H, Fowler HL (2004) Long-term negative impact on quality of life in patients with successfully treated Cushing’s disease. Clin Endocrinol:61(4):458–465. doi:10.1111/j.1365-2265.2004.02118.x

    Article  Google Scholar 

  31. van der Klaauw AA, Kars M, Biermasz NR, Roelfsema F, Dekkers OM, Corssmit EP, van Aken MO, Havekes B, Pereira AM, Pijl H, Smit JW, Romijn JA (2008) Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas. Clin Endocrinol 69(5):775–784. doi:10.1111/j.1365-2265.2008.03288.x

    Article  Google Scholar 

  32. Santos A, Crespo I, Aulinas A, Resmini E, Valassi E, Webb SM (2015) Quality of life in Cushing’s syndrome. Pituitary 18(2):195–200. doi:10.1007/s11102-015-0640-y

    Article  PubMed  Google Scholar 

  33. Song S-K, Yoshino J, Le TQ, Lin S-J, Sun S-W, Cross AH, Armstrong RC (2005) Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage 26(1):132–140. doi:10.1016/j.neuroimage.2005.01.028

    Article  PubMed  Google Scholar 

  34. Fields RD (2008) White matter in learning, cognition and psychiatric disorders. Trends Neurosci 31(7):361–370. doi:10.1016/j.tins.2008.04.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Sexton CE, Mackay CE, Ebmeier KP (2009) A systematic review of diffusion tensor imaging studies in affective disorders. Biol Psychiatry 66(9):814–823. doi:10.1016/j.biopsych.2009.05.024

    Article  PubMed  Google Scholar 

  36. Sexton CE, Allan CL, Le Masurier M, McDermott LM, Kalu UG, Herrmann LL, Mäurer M, Bradley KM, Mackay CE, Ebmeier KP (2012) Magnetic resonance imaging in late-life depression: multimodal examination of network disruption. Arch Gen Psychiatry 69(7):680–689. doi:10.1001/archgenpsychiatry.2011.1862

    Article  PubMed  Google Scholar 

  37. Mazet P, Simon D, Luton JP, Bricaire H (1981) Psychic symptoms and personality of 50 patients with Cushing’s syndrome (author’s transl). La Nouvelle Presse Médicale 10(31):2565–2570

    CAS  PubMed  Google Scholar 

  38. Kim MJ, Whalen PJ (2009). The structural integrity of an amygdala-prefrontal pathway predicts trait anxiety. J Neurosc 29(37):11614–11618. doi:10.1523/JNEUROSCI.2335-09.2009

    CAS  Article  Google Scholar 

  39. Ayling E, Aghajani M, Fouche J-P, van der Wee N (2012) Diffusion tensor imaging in anxiety disorders. Curr Psychiatry Rep 14(3):197–202. doi:10.1007/s11920-012-0273-z

    Article  PubMed  Google Scholar 

  40. Modi S, Trivedi R, Singh K, Kumar P, Rathore RKS, Tripathi RP, Khushu S (2013) Individual differences in trait anxiety are associated with white matter tract integrity in fornix and uncinate fasciculus: preliminary evidence from a DTI based tractography study. Behav Brain Res 238:188–192. doi:10.1016/j.bbr.2012.10.007

    Article  PubMed  Google Scholar 

  41. van den Heuvel DMJ, ten Dam VH, de Craen AJM, Admiraal-Behloul F, Olofsen H, Bollen, ELEM, Jolles J, Murray HM, Blauw GJ, Westendorp RG, van Buchem MA (2006) Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population. J Neurol Neurosurg Psych 77(2):149–153. doi:10.1136/jnnp.2005.070193

    Article  Google Scholar 

  42. Borghesani PR, Madhyastha TM, Aylward EH, Reiter MA, Swarny BR, Schaie KW, Willis SL (2013) The association between higher order abilities, processing speed, and age are variably mediated by white matter integrity during typical aging. Neuropsychologia 51(8):1435–1444. doi:10.1016/j.neuropsychologia.2013.03.005

    Article  PubMed  Google Scholar 

  43. Jacobs HIL, Leritz EC, Williams VJ, Van Boxtel MPJ, van der Elst W, Jolles J, Verhey FR, MC Glinchey RE, Milberg WP, Salat DH (2013) Association between white matter microstructure, executive functions, and processing speed in older adults: the impact of vascular health. Hum Brain Mapp 34(1):77–95. doi:10.1002/hbm.21412

    Article  PubMed  Google Scholar 

  44. Bourdeau I, Bard C, Noël B, Leclerc I, Cordeau M-P, Bélair M, Lesage J, Lafontaine L, Lacroix A (2002) Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism. J Clin Endocrinol Metab 87(5):1949–1954. doi:10.1210/jcem.87.5.8493

    CAS  PubMed  Google Scholar 

  45. Resmini E, Santos A, Gómez-Anson B, Vives Y, Pires P, Crespo I, Portella MJ, de Juan-Delago M, Barahona MJ, Webb SM (2012) Verbal and visual memory performance and hippocampal volumes, measured by 3-Tesla magnetic resonance imaging, in patients with Cushing’s syndrome. J Clin Endocrinol Metab 97(2):663–671. doi:10.1210/jc.2011-2231

    CAS  Article  PubMed  Google Scholar 

  46. Santos A, Resmini E, Crespo I, Pires P, Vives-Gilabert Y, Granell E, Valassi E, Gómez-Ansón B, Martínez-Momblán MA, Mataró M, Webb SM (2014) Small cerebellar cortex volume in patients with active Cushing’s syndrome. Eur J Endocrinol 171(4):461–469. doi:10.1530/EJE-14-0371

    CAS  Article  PubMed  Google Scholar 

  47. Crespo I, Santos A, Gómez-Ansón B, López-Mourelo O, Pires P, Vives-Gilabert Y, Webb SM, Resmini E (2016) Brain metabolite abnormalities in ventromedial prefrontal cortex are related to duration of hypercortisolism and anxiety in patients with Cushing’s syndrome. Endocrine. doi:10.1007/s12020-016-0963-0

    Google Scholar 

  48. Kerchner GA, Racine CA, Hale S, Wilheim R, Laluz V, Miller BL, Kramer JH (2012) Cognitive processing speed in older adults: relationship with white matter integrity. PloS ONE 7(11):e50425. doi:10.1371/journal.pone.0050425

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We want to thank patients and healthy volunteers who participated in the current study for their kind cooperation.

Funding

This project was supported by grants from ISCIII, Spanish Ministry of Science and Innovation (MICINN, FIS080302 and FIS 070770) and the European Commission (ERCUSYN PHP800200).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Beatriz Gómez-Anson.

Ethics declarations

Conflict of interest

Patricia Pires, Alicia Santos, Yolanda Vives-Gilabert, Susan Webb, Aitor Sainz-Ruiz, Eugenia Resmini declares, Iris Crespo, Manuel de Juan-Delago and Beatriz Gómez-Ansón declares that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Research involving animal rights

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pires, P., Santos, A., Vives-Gilabert, Y. et al. White matter involvement on DTI-MRI in Cushing’s syndrome relates to mood disturbances and processing speed: a case-control study. Pituitary 20, 340–348 (2017). https://doi.org/10.1007/s11102-017-0793-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-017-0793-y

Keywords

  • Cushing syndrome
  • Depression
  • Anxiety
  • DTI
  • Brain white matter