Elevated Serum Homocysteine Levels Have Differential Gender-Specific Associations with Motor and Cognitive States in Parkinson’s Disease

Hindawi Parkinson’s Disease Volume 2019, Article ID 3124295, 8 pages https://doi.org/10.1155/2019/3124295 Research Article Elevated Serum Homocysteine Levels Have Differential Gender-Specific Associations with Motor and Cognitive States in Parkinson’s Disease Megan C. Bakeberg ,1,2 Alexa Jefferson,1 Maddeson Riley ,1,3 Michelle Byrnes,1,2 Soumya Ghosh,1,2 Frank L. Mastaglia,1,2 Malcom K. Horne,4,5 Sarah McGregor,5 Rick Stell,1,2 Jade Kenna,1,2 Sue Walters,1,2 Dana Hince,6 and Ryan S. Anderton 1,2,3,6 1 Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia 3 School of Health Sciences, University of Notre Dame Australia, Fremantle, WA, Australia 4 Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia 5 Centre for Clinical Neurosciences and Neurological Research, St Vincent’s Hospital Melbourne, Fitzroy, Victoria, 3065, Australia 6 Institute for Health Research, University of Notre Dame Australia, Fremantle, WA, Australia 2 Correspondence should be addressed to Ryan S. Anderton; Received 21 February 2019; Accepted 23 April 2019; Published 29 May 2019 Academic Editor: Karsten Witt Copyright © 2019 Megan C. Bakeberg et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Studies attempting to elucidate an association between homocysteine and symptom progression in Parkinson’s disease (PD) have had largely discrepant findings. This study aimed to investigate elevated serum homocysteine levels and symptom progression in a cohort of PD patients. Methods. Serum homocysteine, folate, and vitamin B12 levels were measured in 205 people with PD and 78 age-matched healthy controls. People with Parkinson’s disease underwent a battery of clinical assessments to evaluate symptom severity, including motor (MDS-UPDRS) and cognitive (ACE-R) assessments. Multivariate generalised linear models were created, controlling for confounding variables, and were used to determine whether serum markers are associated with various symptom outcome measures. Results. People with Parkinson’s disease displayed significantly elevated homocysteine levels (p < 0.001), but not folate or vitamin B12 levels, when compared to healthy controls. A significant positive correlation between homocysteine and MDS-UPDRS III score was identified in males with Parkinson’s disease (rs � 0.319, p < 0.001), but not in females, whereas a significant negative correlation between homocysteine levels and total ACE-R score was observed in females with Parkinson’s disease (rs � −0.449, p < 0.001), but not in males. Multivariate general linear models confirmed that homocysteine was significantly predictive of MDS-UPDRS III score in male patients (p � 0.004) and predictive of total ACE-R score in female patients (p � 0.021). Conclusion. Elevated serum homocysteine levels are associated with a greater motor impairment in males with Parkinson’s disease and poorer cognitive performance in females with Parkinson’s disease. Our gender-specific findings may help to explain previous discrepancies in the literature surrounding the utility of homocysteine as a biomarker in PD. 1. Introduction Parkinson’s disease (PD) is a chronic and progressive neurological disease that is characterised by the onset of an array of motor and nonmotor signs and symptoms. Nonmotor symptoms, including cognitive impairment, apathy, emotional disturbance, and sleep disturbance, are commonly reported as being equally as debilitating as cardinal motor symptoms [1]. It is well established that the progression and clinical symptom presentation varies considerably among people with Parkinson’s disease (PwP) [2], with some studies indicating that several nonmotor features 2 of PD often precede traditional motor signs [3]. Despite the well-characterised symptomatology of this disease, the specific pathogenic mechanisms underlying the death of such a vast array of neurons and structures cannot yet be explained. Therefore, factors that predict these varying outcomes in PwPs and potential diagnostic biomarkers of this degenerative disease require exploration. Homocysteine (Hcy) is a thiol-containing, nonessential amino acid that is generated in all cells as a by-product of methionine and folate metabolism [4, 5]. Hcy is normally metabolised through two biochemical pathways, during remethylation to methionine and transsulfuration to cystathionine [6]. Therefore, Hcy can accumulate if these biochemical processes become dysregulated [6, 7]. Typically, elevated Hcy levels are associated with increasing age, male gender, caffeine consumption, lack of physical activity, and smoking [7, 8]. Additionally, low levels of dietary vitamin B12 and folate have been associated with elevated serum Hcy, most likely due to the role they have in Hcy metabolism [9, 10]. High levels of serum Hcy, known as hyperhomocysteinemia (HHcy), are thought to contribute to endothelial dysfunction and oxidative damage [7, 11–15]. While previous studies have implicated high levels of serum Hcy in stroke and other cardiovascular disorders [16–18], associations with neurodegenerative disorders such as dementia and Alzheimer’s disease (AD) have also been identified [9, 19]. Several studies have reported an association between HHcy and PD; however, such associations have been thought to be a result of long-term levodopa (L-DOPA) therapy [20, 21]. Interestingly, these studies have also indicated that L-DOPA, itself, may be the principal cause of elevated Hcy levels, as opposed to a consequence of the disease [5, 20–22]. Many studies indicate that elevated Hcy levels can occur independently of PD medication due to genetic variants and nutritional deficiencies of vitamin B12 and folate [23, 24]. Further to this, it is thought that these variants or deficiencies can lead to greater susceptibility to HHcy following levodopa treatment, which is a risk factor for more rapid cognitive decline and progression of motor impairment [20, 25, 26]. To date, investigations into the relationship between elevated Hcy and rate of PD progression and severity have yielded inconsistent results, with variation occurring in studies reporting whether or not HHcy is a risk factor for disease progression [2, 20, 25]. As such, it remains unclear whether HHcy is a significant contributor to PD, or whether disease progression leads to the elevation of Hcy levels [12]. Similarly, the association between elevated levels of Hcy and cognitive dysfunction remains unclear. Findings from a number of studies suggest that elevated Hcy may contribute to the development and exacerbation of cognitive impairment in PD [5, 15, 24, 27–29], and others have reported no association between H (...truncated)