Abstract
Parkinson’s disease (PD) is a progressive and multifactorial neurodegenerative disease. It has been suggested that a dysregulation of the hypothalamic–pituitary–adrenal axis (HPA) occurs in PD. Furthermore, this dysregulation may be involved in triggering, exacerbation or progression of disease. The objective of this study was to systematically review the literature regarding cortisol levels and their relation with motor, cognitive and behavioral symptoms in patients with PD. A systematic search was performed in PubMed and Embase databases, according to PRISMA norms. Twenty-one studies were included, which evaluated baseline levels of cortisol and motor, cognitive, behavioral symptoms, drugs administration or deep brain stimulation to PD treatment. Sample size ranged from 7 to 249 individuals. In 14 studies that assessed cortisol levels in PD patients, seven showed elevation of cortisol levels. In relation to symptomatology, high levels of cortisol were associated with worst functional scores evaluated by UPDRS, depression and behavior in risk preference. Medication interactions showed an influence on the regulation of cortisol release, mainly, conventional drugs used in the PD’s treatment, such as levodopa. The results found in this review point to a possible relationship between cortisol levels and symptoms in PD, indicating that an HPA axis dysfunction related to cortisol level occurs in PD.
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Aarsland D, Marsh L, Schrag A (2009) Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord 24(15):2175–2186. https://doi.org/10.1002/mds.22589
Alatriste-Booth V, Rodríguez-Violante M, Camacho-Ordoñez A, Cervantes-Arriaga A (2015) Prevalence and correlates of sleep disorders in Parkinson’s disease: a polysomnographic study. Arq Neuropsiquiatr 73(3):241–245. https://doi.org/10.1590/0004-282X20140228
Alves G, Forsaa EB, Pedersen KF, Dreetz Gjerstad M, Larsen JP (2008) Epidemiology of Parkinson’s disease. J Neurol 5:18–32. https://doi.org/10.1007/s00415-008-5004-3
Ambrosi G, Cerri S, Blandini F (2014) A further update on the role of excitotoxicity in the pathogenesis of Parkinson’s disease. J Neural Transm (Vienna) 121(8):849–859. https://doi.org/10.1007/s00702-013-1149-z
Augustine EF, Pérez A, Dhall R, Umeh CC, Videnovic A, Cambi F, Wills AM, Elm JJ, Zweig RM, Shulman LM, Nance MA, Bainbridge J, Suchowersky O (2015) Sex differences in clinical features of early, treated Parkinson’s disease. PLoS One 10(7):e0133002. https://doi.org/10.1371/journal.pone.0133002
Bellomo G, Santambrogio L, Fiacconi M, Scarponi AM, Ciuffetti G (1991) Plasma profiles of adrenocorticotropic hormone, cortisol, growth hormone and prolactin in patients with untreated Parkinson’s disease. J Neurol 238(1):19–22. https://doi.org/10.1007/bf00319704
Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR (2015) Oxidative stress and Parkinson’s disease. Front Neuroanat 9:91. https://doi.org/10.3389/fnana.2015.00091
Bocharov EV, Ivanova-Smolenskaya IA, Poleshchuk VV, Kucheryanu VG, Il’enko VA, Bocharova OA (2010) Therapeutic efficacy of the neuroprotective plant adaptogen in neurodegenerative disease (Parkinson’s disease as an example). Bull Exp Biol Med 149(6):682–684. https://doi.org/10.1007/s10517-010-1023-z
Bordet R, Devos D, Brique S, Touitou Y, Guieu JD, Libersa C, Destée A (2003) Study of circadian melatonin secretion pattern at different stages of Parkinson’s disease. Clin Neuropharmacol 26(2):65–72. https://doi.org/10.1097/00002826-200303000-00005
Breen DP, Vuono R, Nawarathna U, Fisher K, Shneerson JM, Reddy AB, Barker RA (2014) Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol 71(5):589–595. https://doi.org/10.1001/jamaneurol.2014.65
Bremmer MA, Deeg DJ, Beekman AT, Penninx BW, Lips P, Hoogendijk WJ (2007) Major depression in late life is associated with both hypo- and hypercortisolemia. Biol Psychiatry 62(5):479–486. https://doi.org/10.1016/j.biopsych.2006.11.033
Bury AG, Pyle A, Elson JL, Greaves L, Morris CM, Hudson G, Pienaar IS (2017) Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease. Ann Neurol 82(6):1016–1021. https://doi.org/10.1002/ana.25099
Cash TV, Lageman SK (2015) Randomized controlled expressive writing pilot in individuals with Parkinson’s disease and their caregivers. BMC Psychol 3:44. https://doi.org/10.1186/s40359-015-0101-4
Chan S, Debono M (2010) Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy. Ther Adv Endocrinol Metab 1(3):129–138. https://doi.org/10.1177/2042018810380214
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909
Demaagd G, Philip A (2015) Parkinson’s Disease and its management: Part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. Pharm Ther 40(8):504–532
Djamshidian A, Lees AJ (2014) Can stress trigger Parkinson’s disease? J Neurol Neurosurg Psychiatry 85:878–881. https://doi.org/10.1136/jnnp-2013-305911
Djamshidian A, O’Sullivan SS, Papadopoulos A, Bassett P, Shaw K, Averbeck BB, Lees A (2011) Salivary cortisol levels in Parkinson’s disease and its correlation to risk behaviour. J Neurol Neurosurg Psychiatry 82:1107–1111. https://doi.org/10.1136/jnnp.2011.245746
Dorszewska J, Prendecki M, Lianeri M, Kozubski W (2014) Molecular effects of L-dopa therapy in Parkinson’s disease. Curr Genom 15:11–17. https://doi.org/10.2174/1389202914666131210213042
Gruden MA, Sewell RD, Yanamandra K, Davidova TV, Kucheryanu VG, Bocharov EV, Bocharova OA, Polyschuk VV, Sherstnev VV, Morozova-Roche LA (2011) Immunoprotection against toxic biomarkers is retained during Parkinson’s disease progression. J Neuroimmunol 233(1–2):221–227. https://doi.org/10.1016/j.jneuroim.2010.12.001
Grünblatt E, Ruder J, Monoranu CM, Riederer P, Youdim MB, Mandel SA (2017) Mandel, differential alterations in metabolism and proteolysis-related proteins in human Parkinson’s disease Substantia nigra. Neurotox Res 33(3):560–568. https://doi.org/10.1007/s12640-017-9843-5
Håglin L, Bäckman L (2016) Covariation between plasma phosphate and daytime cortisol in early Parkinson’s disease. Brain Behav 6(12):e00556. https://doi.org/10.1002/brb3.556
Happe S, Tings T, Helmschmied K, Neubert K, Wuttke W, Paulus W, Trenkwalder C (2004) Levodopa treatment does not affect low-dose apomorphine test in patients with Parkinson’s disease. Mov Disord 19(12):1511–1515. https://doi.org/10.1002/mds.20244
Hartmann A, Veldhuis JD, Deuschle M, Standhardt H, Heuser I (1997) Twenty-four hour cortisol release profiles in patients with Alzheimer’s and Parkinson’s disease compared to normal controls: ultradian secretory pulsatility and diurnal variation. Neurobiol Aging 18(3):285–289. https://doi.org/10.1016/S0197-4580(97)80309-0
Ibrahimagic OC, Jakubovic AC, Smajlovic D, Dostovic Z, Kunic S, Iljazovic A (2016) Psychological stress and changes of hypothalamic–pituitary–adrenal axis in patients with “De Novo” Parkinson’s disease. Med Arch 70(6):445–448. https://doi.org/10.5455/medarh.2016.70.445-448
Kabia FM, Rhebergen D, van Exel E, Stek ML, Comijs HC (2016) The predictve value of cortsol levels on 2-year course of depression in older persons. Psychoneuroendocrinology 63:320–326. https://doi.org/10.1016/j.psyneuen.2015.10.006
Kanner AM (2004) Is major depression a neurologic disorder with psychiatric symptoms? Epilepsy Behav 5(5):636–644. https://doi.org/10.1016/j.yebeh.2004.07.008
Kibel A, Drenjančević-Perić I (2008) Impact of glucocorticoids and chronic stress on progression of Parkinson′s disease. Med Hypotheses 71(6):952–956. https://doi.org/10.1016/j.mehy.2008.06.036
Kluen LM, Agorastos A, Wiedemann K, Schwabe L (2017) Cortisol boosts risky decision-making behavior in men but not in women. Psychoneuroendocrinology 84:181–189. https://doi.org/10.1016/j.psyneuen.2017.07.240
Lemke MR (2008) Depressive symptoms in Parkinson’s disease. Eur J Neurol 1:21–25. https://doi.org/10.1111/j.1468-1331.2008.02058.x
Levy OA, Malagelada C, Greene LA (2009) Greene, Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps. Apoptosis 14(4):478–500. https://doi.org/10.1007/s10495-008-0309-3
Li SY, Wang YL, Liu WW, Lyu DJ, Wang F, Mao CJ, Yang YP, Hu LF, Liu CF (2017) Long-term levodopa treatment accelerates the circadian rhythm dysfunction in a 6-hydroxydopamine rat model of Parkinson’s disease. Chin Med J 130(9):1085–1092. https://doi.org/10.4103/0366-6999.204920
Marakaki C, Papadimitriou DT, Kleanthous K, Papadopoulou A, Papadimitriou A (2015) L-Dopa stimulates cortisol secretion through adrenocorticotropic hormone release in short children. Horm Res Paediatr 84(5):319–322. https://doi.org/10.1159/000439532
Maripuu M, Wikgren M, Karling P, Adolfsson R, Norrback KF (2014) Relative hypo- and hypercortisolism are both associated with depression and lower quality of life in bipolar disorder: a cross-sectional study. PLoS One 9(6):e98682. https://doi.org/10.1371/journal.pone.0098682
Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Bienfait K, Dicke A, Kusnekov A (2010) The role of inflammatory cytokines in cognition and other non-motor symptoms of Parkinson’s disease. Psychosomatics 51:474–479. https://doi.org/10.1176/appi.psy.51.6.474
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) The PRISMA group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
Moore H, Rose HJ, Grace AA (2001) Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons. Neuropsychopharmacology 24:410–419. https://doi.org/10.1016/S0893-133X(00)00188-3
Moreira RC, Zonta MB, Araújo APS, Israel VL, Teive HAG (2017) Quality of life in Parkinson’s disease patients: progression markers of mild to moderate stages. Arq Neuropsiquiatr 75:497–502. https://doi.org/10.1590/0004-282X20170091
Müller T, Muhlack S (2007) Acute levodopa intake and associated cortisol decrease in patients with Parkinson disease. Clin Neuropharmacol 30:101–106. https://doi.org/10.1097/01.WNF.0000240954.72186.91
Müller T, Welnic J, Muhlack S (2007) Acute levodopa administration reduces cortisol release in patients with Parkinson’s disease. J Neural Transm 114:347–350. https://doi.org/10.1007/s00702-006-0552-0
Novakova L, Haluzik M, Jech R, Urgosik D, Ruzicka F, Ruzicka E (2011) Hormonal regulators of food intake and weight gain in Parkinson’s disease after subthalamic nucleus stimulation. Neuro Endocrinol Lett 32:437–441
Pereira GM, Soares NM, Souza AR de, Becker J, Finkelsztejn A, Almeida RMM (2018) Basal cortisol levels and the relationship with clinical symptoms in multiple sclerosis: a systematic review. Arq Neuropsiquiatr 76(9):622–634. https://doi.org/10.1590/0004-282x20180091
Růžička F, Jech R, Nováková L, Urgošík D, Bezdíček O, Vymazal J, Růžička E (2015) Chronic stress-like syndrome as a consequence of medial site subthalamic stimulation in Parkinson’s disease. Psychoneuroendocrinology 52:302–310. https://doi.org/10.1016/j.psyneuen.2014.12.001
Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson's disease. Mov Disord 26(6):1049–1055. https://doi.org/10.1002/mds.23732
Seifried C, Boehncke S, Heinzmann J, Baudrexel S, Weise L, Gasser T, Eggert K, Fogel W, Baas H, Badenhoop K, Steinmetz H, Hilker R (2013) Diurnal variation of hypothalamic function and chronic subthalamic nucleus stimulation in Parkinson’s disease. Neuroendocrinology 97:283–290. https://doi.org/10.1159/000343808
Stypuła G, Kunert-Radek J, Stepień H, Zylińska K, Pawlikowski M (1996) Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson’s disease. Neuroimmunomodulation 3(2–3):131–134. https://doi.org/10.1159/000097237
Tysnes OB, Storstein A (2017) Epidemiology of Parkinson’s disease. J Neural Transm 124:901. https://doi.org/10.1007/s00702-017-1686-y
Vardi J, Oberman Z, Rabey I, Streifler M, Ayalon D, Herzberg M (1976) Weight loss in patients treated long-term with levodopa. Metabolic aspects. J Neurol Sci 30(1):33–40. https://doi.org/10.1016/0022-510X(76)90253-7
Vogel HP, Ketsche R (1986) Effect of hypoglycaemia, TRH and levodopa on plasma growth hormone, prolactin, thyrotropin and cortisol in Parkinson’s disease before and during therapy. J Neurol 233(3):149–152. https://doi.org/10.1007/bf00314421
Volpi R, Caffarra P, Boni S, Scaglioni A, Malvezzi L, Saginario A, Chiodera P, Coiro V (1997) ACTH/cortisol involvement in the serotonergic disorder affecting the parkinsonian brain. Neuropsychobiology 35(2):73–78. https://doi.org/10.1159/000119394
Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OFX, Sousa N, Sotiropoulos I (2016) Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration. Neural Plast. https://doi.org/10.1155/2016/6391686
Walker DG, Lue LF, Serrano G, Adler CH, Caviness JN, Sue LI, Beach TG (2015) Altered expression patterns of inflammation-associated and trophic molecules in Substantia nigra and Striatum brain samples from Parkinson’s disease, incidental Lewy body disease and normal control cases. Front Neurosci 9:507. https://doi.org/10.3389/fnins.2015.00507
Zhang G, Zhang Z, Liu L, Yang J, Huang J, Xiong N, Wang T (2014) Impulsive and compulsive behaviors in Parkinson’s disease. Front Aging Neurosci 6:318. https://doi.org/10.3389/fnagi.2014.00318
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Soares, N.M., Pereira, G.M., Altmann, V. et al. Cortisol levels, motor, cognitive and behavioral symptoms in Parkinson’s disease: a systematic review. J Neural Transm 126, 219–232 (2019). https://doi.org/10.1007/s00702-018-1947-4
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DOI: https://doi.org/10.1007/s00702-018-1947-4