Non-Motor Symptoms in Patients with Parkinson’s Disease – Correlations with Inflammatory Cytokines in Serum

Background Parkinson’s Disease (PD) is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety) are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD. Methods and Materials We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor (sIL-2R) and tumor necrosis factor-α (TNF-α) in blood samples from PD patients (n = 86) and healthy controls (n = 40). Symptoms of fatigue, depression, anxiety and sleeping difficulties were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT), the Hospital Anxiety and Depression Scale (HAD), and the Scales for Outcome in PD-Sleep Scale respectively. Results IL-6 was significantly higher in PD patients than in healthy controls. Compared to healthy controls, PD patients displayed significantly higher mean scores on HAD and lower scores on FACIT, thus indicating more severe symptoms as measured with these scales. Within the PD sample, high levels of both sIL-2R and TNF-α were significantly associated with more severe symptoms assessed by means of FACIT and HAD (depression and anxiety subscales). SIL-2-R levels were able to significantly predict FACIT and HAD scores after the effects of age, gender, anti-parkinsonian medications, and severity of motor symptoms were controlled for. Discussion We suggest that non-motor symptoms in PD patients, such as fatigue and depressive symptoms, might be generated via inflammatory mechanisms. This knowledge might contribute to the development of novel treatment options in PD, specifically targeting non-motor symptoms.

[1]  Masamichi Yokokura,et al.  Neuroinflammation in the living brain of Parkinson's disease. , 2009, Parkinsonism & related disorders.

[2]  P Riederer,et al.  Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. , 1995, Neuroscience letters.

[3]  G. Huston.  The Hospital Anxiety and Depression Scale. , 1987, The Journal of rheumatology.

[4]  H. Marín,et al.  The role of inflammatory cytokines in cognition and other non-motor symptoms of Parkinson's disease. , 2010, Psychosomatics.

[5]  Kendall A. Smith,et al.  Interleukin-2: inception, impact, and implications. , 1988, Science.

[6]  Peter Riederer,et al.  Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients , 1995, Neuroscience Letters.

[7]  B. Leikind,et al.  An Assessment of , 2011 .

[8]  I. Katz,et al.  Effect of Psychiatric and Other Nonmotor Symptoms on Disability in Parkinson's Disease , 2004, Journal of the American Geriatrics Society.

[9]  H. Möller,et al.  The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine , 2006, Molecular Psychiatry.

[10]  C. Clarke,et al.  Systematic review of levodopa dose equivalency reporting in Parkinson's disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[11]  I. Katz,et al.  Antidepressant studies in Parkinson's disease: A review and meta‐analysis , 2005, Movement disorders : official journal of the Movement Disorder Society.

[12]  H. Stolze,et al.  Defective production of interleukin-2 in patients with idiopathic Parkinson's disease , 1995, Journal of the Neurological Sciences.

[13]  L A Rubin,et al.  The soluble interleukin-2 receptor: biology, function, and clinical application. , 1990, Annals of internal medicine.

[14]  E. Katunina,et al.  [Epidemiology of Parkinson's disease]. , 2013, Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova.

[15]  H. Przuntek,et al.  Interleukin-6 levels in cerebrospinal fluid inversely correlate to severity of Parkinson's disease. , 1998, Acta neurologica Scandinavica.

[16]  B. Ferger,et al.  Inhibition of the cyclooxygenase isoenzymes COX‐1 and COX‐2 provide neuroprotection in the MPTP‐mouse model of Parkinson's disease , 2001, Synapse.

[17]  K. Mohanakumar,et al.  Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats , 2003, Brain Research.

[18]  M. Tansey,et al.  Modeling neuroinflammatory pathogenesis of Parkinson's disease. , 2010, Progress in brain research.

[19]  R C Grace,et al.  A profile of neuropsychiatric problems and their relationship to quality of life for Parkinson's disease patients without dementia. , 2008, Parkinsonism & related disorders.

[20]  R. Dobbs,et al.  Association of circulating TNF‐α and IL‐6 with ageing and parkinsonism , 1999 .

[21]  D. Baldwin,et al.  A neuroimmunological perspective on anxiety disorders , 2012, Human psychopharmacology.

[22]  M. Tansey,et al.  Neuroinflammation and Non-motor Symptoms: The Dark Passenger of Parkinson’s Disease? , 2012, Current Neurology and Neuroscience Reports.

[23]  P. Hagell,et al.  Towards an understanding of fatigue in Parkinson disease , 2009, Journal of Neurology, Neurosurgery, and Psychiatry.

[24]  J. Friedman,et al.  Neuropsychiatric symptoms in Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[25]  P. Andersen,et al.  Major depressive disorder in Parkinson's disease: a register‐based study , 2002, Acta psychiatrica Scandinavica.

[26]  C. Caruso,et al.  Biological significance of soluble IL-2 receptor , 1993, Mediators of inflammation.

[27]  Jin-Mann S. Lin,et al.  Association of peripheral inflammatory markers with chronic fatigue in a population-based sample , 2009, Brain, Behavior, and Immunity.

[28]  T. Krahn,et al.  Elevated plasma levels of TNF-alpha and Interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders , 2009, Cardiovascular diabetology.

[29]  M. Wichers,et al.  Erratum to “Cytokines and major depression” [Prog. Neuropsychopharmacol. Biol. Psychiat. 29(2) (2005) 201–217] , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[30]  Y. Ben-Shlomo,et al.  Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies. , 2011, The Cochrane database of systematic reviews.

[31]  R. Ho,et al.  Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. , 2012, Journal of Affective Disorders.

[32]  R. Shamloul,et al.  Sleep Disturbances in Parkinson's Disease , 2010 .

[33]  S. Gilman,et al.  Diagnostic criteria for Parkinson disease. , 1999, Archives of neurology.

[34]  Gert Jan Lammers,et al.  Assessment of sleep and sleepiness in Parkinson disease. , 2003, Sleep.

[35]  R. Dobbs,et al.  Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism. , 1999, Acta neurologica Scandinavica.

[36]  Jeremy Holmes,et al.  Direct economic impact of Parkinson's disease: A research survey in the United Kingdom , 2003, Movement disorders : official journal of the Movement Disorder Society.

[37]  C. Barnum,et al.  Exogenous corticosterone reduces l-DOPA-induced dyskinesia in the hemi-parkinsonian rat: Role for interleukin-1β , 2008, Neuroscience.

[38]  B. Ritz,et al.  Occurrence of depression and anxiety prior to Parkinson's disease. , 2010, Parkinsonism & related disorders.

[39]  Martin Samuelsson,et al.  Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity , 2009, Biological Psychiatry.

[40]  A. Teixeira,et al.  Serum levels of interleukin-6 are elevated in patients with Parkinson's disease and correlate with physical performance , 2010, Neuroscience Letters.

[41]  M. Wichers,et al.  Cytokines and major depression , 2005, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[42]  S. Akhondzadeh,et al.  Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial , 2009, Depression and anxiety.

[43]  P. Svenningsson,et al.  Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression , 2010, Journal of Neurology.

[44]  R. Dantzer,et al.  Named Series: Twenty Years of Brain, Behavior, and Immunity Twenty years of research on cytokine-induced sickness behavior , 2007 .

[45]  Meg E Morris,et al.  Determinants of health-related quality of life in Parkinson's disease: a systematic review. , 2011, Parkinsonism & related disorders.

[46]  M. Onofrj,et al.  Peripheral cytokines profile in Parkinson’s disease , 2009, Brain, Behavior, and Immunity.