Biomarkers in Neurodegenerative Diseases: Cortisol

Neurodegenerative diseases are characterized by progressive loss of cognitive function, dementia, and problems with movements. Identification of biomarkers during disease process, induce to an effective and early diagnostic test for neurodegenerative diseases. These biomarkers would allow presymptomatic disease detection of disease and would be valuable for monitoring the efficacy of disease. Cortisol is a biomarker used for stress evaluation and a potential neurodegenerative disease biomarker. Objective: The aim of this paper is to review systematically the scientific literature about evaluation to cortisol biomarker in neurodegenerative diseases. Methods: Systematic literature review on Pubmed, Medline and Scopus database with the keywords "cortisol biomarkers” and "neurodegenerative diseases". It was analyzed all existing articles (between 1988 and 2015). PRISMA criteria reporting of systematic reviews and meta-analyses were applied. The inclusion criteria were: cortisol biomarkers in neurodegenerative diseases diagnosis, presenting quantitative or qualitative results. It was excluded articles outside the scope of the subject and articles with unavailable information. Results: After applying the methodology, 14 scientific articles were included in the study. So, these studies were analyzed. Conclusions: This paper review based on the contribution of cortisol biomarkers to diagnose and treat neurodegenerative diseases. for neurodegenerative processes [1,10]. There is a need for additional and more sensitive biomarkers for the early and differential diagnosis of different neurodegenerative disease [6]. Identification of preclinical biomarkers for neurodegenerative diseases has led to new insights concerning disease pathophysiology and time course and has disclosed some interesting parallels in these common neurodegenerative diseases. Body fluids, such as cerebrospinal fluid (CSF), serum, saliva, blood or urine, offer an attractive medium to biomarker analysis [5,10-15]. The firsts biochemical biomarkers of neurodegenerative diseases were: the proteins beta-amyloid (Aβ), total tau and its phosphorylated forms (p-tau) measured in cerebrospinal fluid (CSF), but, these markers are dependent upon invasive lumbar puncture and therefore appear less amenable for high through screening of patients [11,13,15]. There is a pressing need for new biomarkers in more easily accessible body fluids such as peripheral blood [6,8,13]. Nowadays, recent studies prove that blood-based testing would be widely available, non-invasive, easy, economic and rapid to perform. In this review, we analyzed the paper of cortisol biomarker in neurodegenerative disease. Citation: Batista P, Pereira A (2016) Biomarkers in Neurodegenerative Diseases: Cortisol. J Mol Biomark Diagn 7: 277. doi:10.4172/2155-9929.1000277

Nowadays, symptomatic treatments exist, but there are currently no effective drugs to reverse or halt the progression of the diseases. Improving the early and predictive diagnosis of neurodegenerative diseases is the paramount importance and enormous efforts are under way [6][7][8].
Therefore, it is required a tool to aid physicians, epidemiologists, and scientists in the study of human diseases by confirming a diagnosis and tracking disease progression, which may help to identify specific therapeutic targets.
So, development of biomarkers may measure disease risk, presence, and progression is one of the main goals and challenges in research in neurodegenerative diseases [8,9].
For National Institutes of Health (NIH) a biomarker is "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention" (2001).
Advances in biochemistry (neurochemistry, proteomics, genomics) have increased our understanding of the central nervous system at the molecular level and applied us to screen for new biomarkers specific Cortisol is a steroid hormone and the most important human glucocorticoid, and regulates a variety of important cardiovascular, metabolic, immunological, homeostatic, and brain functions (brain metabolism, gene expression, and memory) [3,[16][17][18]. Cortisol levels are known to increase within minutes of a stressful event, and high cortisol levels increase activity of the hypothalamus-pituitary-adrenal (HPA) axis [4,5,17,18].
Therefore, the aim of this paper is to systematically review the scientific literature about evaluation to cortisol biomarker in neurodegenerative diseases.

Methods
We conducted a study of reflective systematic literature review. Between 1998 and 2015, we identified scientific papers published in international journals, using a search of the databases in digital format, MedLine and PubMed, and a second phase to Scopus. The descriptors used in the research were: ["biomarkers" and "neurodegenerative diseases"]. Time later, because of the high number of matches (11843 publications), the research was refined to ["cortisol biomarkers" and "neurodegenerative diseases"], having been obtained 34 publications. The study was restricted to English articles published. The research with the final descriptors ["cortisol biomarkers" and "neurodegenerative diseases"] resulted in 34 publications in PubMed database, 16 publications in MedLine and 16 publications in Scopus. Analyzed 34 publications obtained in the PubMed database, form excluded 20 publications: 16 publications were outside the scope of the study and 4 articles with unavailable information.
The inclusion and exclusion criteria of the studies are described: a) Inclusion: cortisol biomarkers in neurodegenerative diseases diagnosis, presenting quantitative or qualitative results. b) Exclusion: other biomarkers in neurodegenerative diseases, no presenting quantitative or qualitative results and articles with unavailable information.
PRISMA criteria for preferred reporting items for systematic reviews and meta-analyzes (Prisma)ª were applied. The information collected was compiled and analyzed with respect to the year of publication, authors, sample and country, type of study/methodology, results and aim.
The cataloguing and identification of repeated references were made through the computer program EndNote bibliographic referencing ( Figure 1).

Analysis of Results and Discussion
For a better understanding of the systematic literature review, studies analyzed were compiled in a summary It was analyzed fourteen complete articles which met the inclusion criteria.
A total of 4361 adults from four different countries (United States, Canada, Germany, Poland, Australia, France, Switzerland, Sweden and Japan) were analyzed. Different dimensions to evaluate biochemical parameters, physical, neurological and psychiatric dimensions. Similarly, many instruments were used to measure different dimensions were analyzed.
Cross-sectional and longitudinal studies methodologies were present in this review.    The current review revealed many studies about biomarkers in neurodegenerative diseases, but few studies about "Cortisol biomarkers in Neurodegenerative diseases". Development of biomarkers that may measure disease risk, presence, and progression is one of the main goals and challenges in research in neurodegenerative diseases.
The availability of neuroimaging and biomolecular biomarkers to monitor and control brain changes structures, inflammatory processes and other biochemical pathways enable investigation of pathways that may be related to neurodegenerative disease [5,19,20].
Biomarkers for these pathologies are of great value as diagnostic aids (especially early in the course of the disease, when the clinical symptoms are vague and diagnosis are difficult), therefore, these biomarkers should reflect the central pathogenic processes of the diseases.
Laske et al., identified three blood markers, involved in several biological pathways including cardiovascular, metabolic, immunological, homeostatic, and brain functions (cortisol), oxidative stress and antioxidant response (OLAB), and endothelial dysfunction (vWF), which have been associated with the pathogenesis of AD [18]. Soares describe a list of biomarkers identified within the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort and Doecke present biomarkers identified (cortisol, IGFBP2, and PPY) within the Australian Imaging, Biomarkers and Lifestyle (AIBL) study [13,14]. These data indicate that further research validating cortisol levels across different neurologic diseases is required to determine its specificity [13].
Other studies about cortisol, indicate that it might independently cause brain atrophy and the increase (peripheral and central) of the nervous system cortisol levels have been reported in neurodegenerative diseases (Alzheimer's disease) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis [5,15,20]. Most studies focusing on HPA axis and cortisol in patients with AD have measured plasma, CSF or salivary cortisol levels, but, in humans, only a few observational studies have investigated whether increased salivary or plasma cortisol levels predict a more rapid disease progression in AD, reporting inconclusive results [5,14,21,22].
The HPA axis is a neuroendocrinological system that regulates the circulation of cortisol concentration in response to psychological and physical stress. It is implicated in a number of physiological pathways and functions including the sleep wake cycle, mood, cognition, energy storage and metabolism, digestion, sexual behaviour, and the immune system; many of which are disturbed in HD. HPA axis abnormalities and heightened cortisol levels have been identified in HD [4]. HPA axis hyperactivity with increased cortisol levels may be not only an early event in the course of AD but also a factor precipitating cognitive decline and clinical worsening over time. Nevertheless, the role of hypercortisolism in the pathogenesis and progression of AD remains a subject of controversy.
However, brain exposure to high cortisol concentrations may also accelerate disease progression, pathophysiological process, and accelerate clinical disease progression [5].
Elevated cortisol levels have also been associated with reduced learning and memory abilities in normal aging [4]. Shirbin suggest that dysregulation of cortisol concentrations may be involved in the decline of verbal learning and memory recall ability in patients with HD, but did not find relations between recognition memory performance and cortisol levels [4]. The verbal learning and memory deficits identified in this study may be related to hippocampal dysfunction due to abnormally high cortisol levels that is similar to the profile of other disorders that also display abnormal hippocampal morphology associated with dysregulated HPA axis activity, such as AD and major depressive disorder [4,12,17,23].
These study suggest HPA axis hyperactivity may begin in the pre-HD stage with a prolonged period of hypercortisolism damaging the hippocampus, and functional learning and memory deficits might only become evident after transitioning to the early-HD stage and unequivocal HD motor signs are displayed [4]. Also, hypothalamic pathology in pre-HD and HD patients suggests that the hypothalamus is a plausible root cause of abnormal cortisol concentrations (especially higher cortisol levels) [4].
Shirbin et al. mentioned the cortisol neurotoxicity hypothesis, hippocampus induces a continuum cycle of dysregulated high cortisol levels and ongoing hippocampal degeneration [4]. High stress may be influence toxic effect, as observed in other studies which have indicated associations between prolonged stress, high cortisol, hippocampal damage, and learning and memory deficits [4]. This study was the first to report the utility of cortisol levels as a biomarker of cognitive decline in HD [4].
Also, Gruber et al. analyzed some parameters in the plasma samples which may potentially discriminate controls and HD patients [24]. Concerning amino acid profile and biochemical markers, Canonical Discriminant Analysis detected a panel of variables (Ser, Asn, Gln, Orn, Pro, Arg, Met, Cit, Val, TSH, glucose, urea, creatinine clirens, total protein, cortisol, CRP). Asn and Ser were revealed in all statistical analyses and could be considered as a potential plasma HD biomarkers, but more search is needed for HD plasma biomarkers [24].
Other studies mentioned that the increased plasma levels of cortisol and C-reactive protein prove increased anxiety, stress, depression and inflammatory component in the symptoms reported in HD [24]. Likewise, cortisol was correlated with clinical status and depressive mood in ALS patients [3].
The cortisol awakening response in ALS is blunted, and Roozendaal et al. analyze this problem [3]. They concluded, as previous findings indicates, that particularly the rise in cortisol levels immediately after awakening, the cortisol awakening response (CAR), is associated with indices of physical and emotional well-being. Their data indicates that ALS patients show a blunted CAR, correlated with disease (poorer clinical status) and severe depressive status. Thus, ALS patients may be a consequence of the emotional or physical distress and associated symptoms of chronic fatigue and depression. These results suggest a reduced responsivity of the HPA-axis in ALS [3].
Beyond the depression, epidemiological evidence that cardiovascular risk factors (CVRF) are risk factors for Alzheimer's disease, but there is limited information on this from neuropathological studies. Cortisol has been related to Aβ deposition and memory deficits in normal transgenic mice and to hippocampal atrophy in human brain magnetic resonance imaging studies [15]. Therefore, we examined the relationship between CVRF and amyloid-β (Aβ) brain burden measured by Pittsburgh Compound B-positron emission tomography (PiB-PET) studies in the Alzheimer's Disease Neuroimaging Initiative [15]. This study confirms the relation between cortisol and brain Aβ deposition in human subjects [15].

Summary of Methodological Limitations
Numerous articles have been developed in the field of biomarkers to the application in neurodegenerative diseases, and search was more restricted.
The selected biomarker can´t be the one with the most reliable results and making the limited study.
The use of a single measuring instrument, would have allowed an easier and more correct comparison of the identified variables.
We found limitations in the analyzed articles: small number the subjects [4,11,24]; longer follow-up in larger samples of participants [5]; difficult to be precise about the interdependence of the parameters [24]; allowing more detailed consideration for the impact of stress, [4]; difficulties in longitudinal epidemiological studies is to discern the underlying pathology or pathologies [15]; small longitudinal studies [14]; little salivary cortisol collections [3], diurnal variability in cortisol levels [18].

Implications for Practice
Neurodegenerative disorders are a heterogeneous group of disorders characterized by a progressive and selective loss of anatomically or physiologically related neuronal systems that is affecting people of all ages (affects older and some young adults). Although in these diseases, the mechanisms are still far from being clarified. Future studies are needed to investigate the neurological or psychological mechanisms underlying this alteration in HPA responsivity.
In recent years, there has been a growing interest in applying biomarkers to research on prognosis and treatment of neurodegenerative diseases.
This literature review, suggest new studies about biomarkers in neurodegenerative diseases.
More studies are important to understand the mechanism and actuation of biomarkers in diagnosis and treatment of these diseases.

Conclusion
Neurodegenerative diseases are a growing problem worldwide, given the rapidly ageing population, the current search for biomarkers is very important.
Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases (for example, neuronal degeneration).
There is an urgent need for biomarkers to diagnose neurodegenerative diseases early in their course, to differentiate them from other related diseases or subtypes, and to monitor responses of patients to new therapies.