title: MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies.
abstract: BACKGROUND
  Cushing's syndrome (CS) is characterized by excessive exposure to cortisol, and is associated with both metabolic and behavioral abnormalities. Symptoms improve substantially after biochemical cure, but may persist during long-term remission. The causes for persistent morbidity are probably multi-factorial, including a profound effect of cortisol excess on the brain, a major target area for glucocorticoids.
  
  
  OBJECTIVE
  To review publications evaluating brain characteristics in patients with CS using magnetic resonance imaging (MRI).
  
  
  METHODS
  Systematic review of literature published in PubMed, Embase, Web of Knowledge, and Cochrane databases.
  
  
  RESULTS
  Nineteen studies using MRI in patients with CS were selected, including studies in patients with active disease, patients in long-term remission, and longitudinal studies, covering a total of 339 unique patients. Patients with active disease showed smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy as well as alterations in neurochemical concentrations and functional activity. After abrogation of cortisol excess, the reversibility of structural and neurochemical alterations was incomplete after long-term remission. MRI findings were related to clinical characteristics (i.e., cortisol levels, duration of exposure to hypercortisolism, current age, age at diagnosis, and triglyceride levels) and behavioral outcome (i.e., cognitive and emotional functioning, mood, and quality of life).
  
  
  CONCLUSIONS
  Patients with active CS demonstrate brain abnormalities, which only partly recover after biochemical cure, because these still occur even after long-term remission. CS might be considered as a human model of nature that provides a keyhole perspective of the neurotoxic effects of exogenous glucocorticoids on the brain.
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands c.d.andela@lumc.nl.
authors: Cornelie D
authors: CD
authors: Andela
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Femke M
authors: FM
authors: van Haalen
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Oskar
authors: O
authors: Ragnarsson
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Eleni
authors: E
authors: Papakokkinou
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Gudmundur
authors: G
authors: Johannsson
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Alicia
authors: A
authors: Santos
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Susan M
authors: SM
authors: Webb
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Nienke R
authors: NR
authors: Biermasz
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Nic J A
authors: NJ
authors: van der Wee
authors: Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands Department of MedicineDivision of Endocrinology and Center for Endocrine Tumors, Leiden University Medical Center, Leiden, The NetherlandsLeiden Institute for Brain and CognitionLeiden, The NetherlandsDepartment of Endocrinology Diabetes and MetabolismSahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenEndocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of PsychiatryLeiden University Medical Center, Leiden, The Netherlands.
authors: Alberto M
authors: AM
authors: Pereira
mesh_terms: D001921:Brain / Q000473:pathology*; D003480:Cushing Syndrome / Q000150:complications / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D020127:Recovery of Function