|Year : 2019 | Volume
| Issue : 4 | Page : 164-170
Circulating brain-derived neurotrophic factor level in patients with primary open angle glaucoma
Ahmed Saidu1, Sadiq Hassan2, Ahmadu Shehu Mohammed3, Isyaku Umar Yarube4
1 Medical Services Branch, Headquarters, Nigerian Air Force, Abuja, Nigeria
2 Department of Ophthalmology, Faculty of Clinical Sciences, College of Health Sciences, Aminu Kano Teaching Hospital, Bayero University, Kano, Nigeria
3 Nigeria Navy Medical Services, Naval Medical Centre, Victoria Island, Lagos, Nigeria
4 Department of Physiology, Neuroscience and Pathophysiology Unit, Faculty of Basic Medical Sciences, College of Health Sciences, Bayero University, Kano, Nigeria
|Date of Submission||21-Apr-2018|
|Date of Acceptance||22-Mar-2019|
|Date of Web Publication||29-Nov-2019|
Dr. Isyaku Umar Yarube
Department of Physiology, Neuroscience and Pathophysiology Unit, Bayero University, Kano
Background: Glaucoma constitutes a serious health problem in Nigeria and beyond. It is a leading cause of bilateral blindness and its burden remains high. There is a paucity of literature on the levels of circulating brain-derived neurotrophic factor (BDNF) in health and disease among Africans. In addition, the dynamics and reasons for variation in the levels of BDNF in the local population of glaucoma patients are yet to be demonstrated. Objective: This study determined the circulating level of BDNF and factors associated with it among glaucoma patients. Materials and Methods: Serum concentration of BDNF and other oculo-visual and sociodemographic characteristics were determined in glaucoma patients and controls. Data were processed using IBM SPSS Statistics version 20. Results: Forty-four adult glaucoma patients of both sexes and 41 nonglaucoma controls matched for age and sex with an average age of about 50 years were studied. BDNF level among the glaucoma patients was higher (2.578 ± 1.394) than that of the controls (1.745 ± 0.707) (t = 3.436, P = 0.001). Glaucoma patients who were blind had the lowest levels of circulating BDNF (P = 0.022); the level of BDNF in the naïve patients (not yet placed on medication) is about five times less than in those patients placed on medication (P = 0.001). Circulating BDNF was associated with glaucoma treatment among the patients. Conclusion: The level of circulating BDNF in primary open angle glaucoma patients on treatment is high than those who were not on treatment. It influenced by coexisting medical conditions.
Keywords: Brain-derived neurotrophic factor, glaucoma, oculo-visual symptoms
|How to cite this article:|
Saidu A, Hassan S, Mohammed AS, Yarube IU. Circulating brain-derived neurotrophic factor level in patients with primary open angle glaucoma. Sahel Med J 2019;22:164-70
|How to cite this URL:|
Saidu A, Hassan S, Mohammed AS, Yarube IU. Circulating brain-derived neurotrophic factor level in patients with primary open angle glaucoma. Sahel Med J [serial online] 2019 [cited 2020 Sep 29];22:164-70. Available from: http://www.smjonline.org/text.asp?2019/22/4/164/272146
| Introduction|| |
Glaucoma constitutes a serious health problem worldwide. The burden of glaucoma has remained highly significant worldwide despite advances made in diagnosis and treatment modalities. A study confirmed a higher prevalence of glaucoma in African-Americans than in Caucasian-Americans-prevalence of any glaucoma in white populations ranged from 1 to 1.5% in those aged 40–65 years, rising to 2%–7% in those older than 65; estimates in black Americans ranged from 1.5% to 3.6% and 4.6% to 9.8%, respectively, for similar age groups. According to the Nigerian National Blindness Survey, glaucoma accounts for 16.7% of blindness in the over 40 years age group with estimated glaucoma-related blindness of 0.7% among Nigerian adults. The number of people who are blind due to glaucoma is projected to hit over 11 million by the year 2020.
In primary open angle glaucoma (POAG), the most common form of glaucoma, the anterior chamber angle is open and the structures are visible on gonioscopy. POAG is characterized by selective death of retinal ganglion cells (RGC's) and their respective axons, resulting in asymmetric changes in the optic cup, with corresponding visual field loss.
Glaucoma is a complex multifactorial neurodegenerative disease with multiple pathogenic mechanisms, including raised intraocular pressure (IOP), defective autoregulation and ischemia, glutamate-mediated exicitotoxicity, immune-related phenomenon, intracellular calcium influx and free radical damage, and vascular dysregulation., The molecular mechanisms invoked largely include glutamate excitotoxicity, increased matrix metalloproteinase expression, tumor necrosis factor-alpha up-regulation, increased nitric oxide syntheses-2 expression, and oxidative stress.
Study has shown that the accelerated apoptosis of the RGC's in glaucoma is related to neurotrophic factor deficiency., An example of a neurotrophic factor (neurotrophin), is brain-derived neurotrophic factor (BDNF), a polypeptide which is a vital component for building up and preserving neurons. BDNF is the most abundant neurotrophin in the brain and essential for neuronal survival during development and for the integration of neurons in the adult brain. It is also expressed in the liver and skeletal muscle and is pivotal for the normal development of the cardiovascular system. In the blood, BDNF is mainly stored in thrombocytes, with only a minor free fraction in plasma. Blood BDNF concentrations correlate positively with BDNF levels in the hippocampus of rats and pigs.
Neurotrophic factors could serve as useful biomarkers for the diagnosis of glaucoma. Biomarkers are molecules with biologically important function, expression or activity of which either causes or is specifically altered in response to the corresponding pathological condition. Neurotrophic factors could also serve as therapeutic targets for treatment of the disease since the use of neuron-survival (neurotrophic) agents was suggested to be a potentially efficient way of achieving preservation of RGC function and subsequently maintaining vision in glaucoma. However, the role and dynamics of BDNF in the pathophysiology of glaucoma has not been fully elucidated. In addition, there is a paucity of literature on the levels of circulating BDNF in Africans, despite black race being an additional risk factor for glaucoma. This study, therefore, sought to evaluate the circulating levels of BDNF and factors associated with it.
| Materials and Methods|| |
Study setting and design
The study was conducted at Murtala Mohammed Specialist Hospital (MMSH), located in the city of Kano, northwest Nigeria. MMSH is a 250-bed hospital with 20 departments and units, among which is the eye clinic, where the patients were recruited for the study. The eye clinic at the MMSH is a 30-bed capacity eye unit conducting 3 clinic days in a week, in which an average of 200 patients is seen on each clinic day, making a monthly turnover of nearly 2400 patients. Of this, about 30 patients are glaucoma patients seen on each clinic day, making about 360 glaucoma patients seen per month.
All patients with POAG were eligible for the study. POAG patients with ocular conditions such as optic neuropathy other than POAG, retinal vascular occlusive disease, any other retinal or choroidal disease, previous ocular surgery, significant cataract or cataract surgery within the past 6 months, age-related macular degeneration, and high myopia were excluded from the study. So also were patients with a history or evidence of stroke, diabetes mellitus, any drug abuse, smoking, alcohol dependence, and any neuropsychiatric illness or treatment. Apparently, healthy first-degree relatives of the patients and other nonglaucoma volunteers served as controls. Ethical approval was obtained from the Kano State Ministry of Health (Ref.: MOH/Off/797/T. I./97, dated May 3, 2016). Signed informed consent was obtained from each participant before the commencement of data collection. The study conformed to the Declaration of Helsinki.
The sample size was determined using computer software for power sample size determination according to Lenth. We conducted a pilot study to obtain BDNF value (mean ± standard deviation [SD]) of 1.796 ± 0.71 for the purpose of computing the sample size for this study, assuming statistical power of 86%. Systematic sampling, with a sampling interval of 8 was used to recruit 44 male and female patients into this cross-sectional study.
Patients with established diagnosis of POAG were studied. The diagnosis of POAG was made by trained personnel based on optic disc abnormalities, reproducible visual field defects typical of glaucoma as determined by the Humphrey field analyzer (Carl Zeiss, Germany) (S1TA full-threshold program 30-2) and open anterior chamber angles on gonioscopy. Assessment of the optic disc was made by fundoscopy using the handheld direct ophthalmoscope (Welch Allyn, USA). Optic disc abnormalities included a localized notch in the neuroretinal rim or generalized rim thinning defined as glaucomatous cupping of the disc. A cup-disc ratio of <0.5 was classified as nonsignificant, whereas that of 0.5 and above was classified as significant optic nerve damage.
Sociodemographic data, medical/ocular history, oculo-visual data, and other clinical characteristics were obtained and documented in a data capture form specially designed for the study. Samples of venous blood were collected from patients between 9 a.m. and 11 a.m. to minimize the possible effects of circadian rhythms on BDNF concentrations. The samples were allowed to clot for 2 h at room temperature before centrifugation for 15 min at 1000 g. Serum was extracted from the samples and BDNF concentrations were determined using the BDNF Human ElIZA Kit (E-EL-H0010) (Elabscience Biotechnology Co. Ltd., USA) according to the manufacturer's directions.
Values were expressed as frequency or mean ± SD and 95% of confidence interval (CI). Sociodemographic features were compared using the Mann–Whitney U-test, whereas BDNF was compared based on different oculo-visual features using the Independent samples t-test or ANOVA as appropriate. Relationship between BDNF and oculo-visual features was evaluated using the Kendall's tau-b or Chi-square. Values of P were considered statistically significant when <0.05. Version 20 IBM SPSS Statistics (SPSS Inc., Il, U.S.A.) was employed for data analysis.
| Results|| |
A total of 85 participants comprising 44 glaucoma patients and 41 nonglaucoma controls were studied. The mean age of the glaucoma patients (51.9 ± 15.3 years, 95% CI of 47.2–56.5) and controls (52.6 ± 14.2 years, 95% CI of 48.1–58.1) was not significantly different (t = −0.226, P = 0.822). The sociodemographic features of the participants indicate no significant difference in age and gender composition. However, there was significantly higher proportion of urban than rural dwellers among glaucoma patients compared to controls [Table 1].
In addition, the glaucoma patients differed significantly from the controls in terms of the past ocular history, family history of glaucoma, visual acuity of the right eye, visual acuity of the left eye, level of visual impairment, the severity of optic nerve damage in the right eye, and the severity of optic nerve damage in the left eye (Mann–Whiney U = 676.6 and P = 0.001, U = 472.0 and P = 0.001, U = 328.0 and P = 0.001, U = 389.5 and P = 0.001, U = 521.5 and P = 0.001, U = 184.5 and P = 0.001, U = 164.0 P = 0.001, respectively).
Circulating BDNF level among the glaucoma patients (2.578 ± 1.394, 95% CI = 2.154–3.002) was significantly higher than that of the controls (1.745 ± 0.707, 95% CI = 1.522–1.968) (t = 3.436, P = 0.001). [Table 2] contains mean BDNF values of glaucoma patients and controls classified based on their oculo-visual features; table also contains within-glaucoma-group comparison of the BDNF values for significant differences to examine which of these features is a reason for variation of circulating BDNF among the patients. There was a statistically significant variation of BDNF based on the level of visual impairment of the patients (P = 0.022); the patients with the worst visual impairment (blindness) had the lowest levels of circulating BDNF. Medication was also a reason for significant variation of circulating BDNF in the patients (P = 0.001); the level of BDNF in the naïve patients (not yet placed on medication) is about five times less than in those patients placed on medication. However, BDNF did not vary based on all the other oculo-visual features examined.
|Table 2: Variations of circulating brain-derived neurotrophic factor according to oculo-visual features of glaucoma patients|
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The relationship (correlation for the duration of glaucoma or association for other features) between BDNF and the oculo-visual features of the glaucoma patients was determined and summarized in [Table 3]. Circulating BDNF was significantly associated with coexisting medical conditions in the patients and glaucoma medications. There was no relationship between serum BDNF and all the other features examined.
|Table 3: Relationship between circulating brain-derived neurotrophic factor level and oculo-visual features of glaucoma patients|
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| Discussion|| |
This study evaluated circulating BDNF levels in glaucoma patients and normal nonglaucoma controls matched for age and gender, but with predominance of urban dwellers among the glaucoma patients. Only about half of the glaucoma patients presented with the complaint of poor vision, which shows how glaucoma can remain symptomless in many cases, thereby leading to late diagnosis. However, nearly one-fifth of the patients were blind in contrast to the controls who presented with normal visual function. This portrays the symptomless nature of the condition in the early stages and also the fact that patients present to the clinic when the level of visual impairment had reached an advanced stage. This result corroborates previous studies that adjudged glaucoma as a leading cause of bilateral blindness.,,
Primary glaucoma has no known definite cause. However, there are some established risk factors known to contribute to the development of the disease. Recognized risk factors for glaucoma include elevated IOP, age, race, family history, myopia, and central corneal thickness. This study revealed that family history of glaucoma was more common among the glaucoma patients than among the controls, with more than half of the glaucoma patients having a positive family history, compared to only about one-tenth of the normal controls. This is in conformity with the findings of Coleman andMiglior  who reported that family history is a strong risk factor for the development of glaucoma. There is a strong correlation between POAG and the presence of the disease in the first-degree relatives. Population-based studies have demonstrated a higher prevalence of glaucoma among siblings and offspring of patients with glaucoma compared to relatives of controls. Furthermore, this is also in line with the findings of the Baltimore Eye Survey, in which the prevalence of glaucoma was much higher in siblings and offspring of patients with glaucoma than in relatives of controls.
Although most of the glaucoma patients in this study were on glaucoma medications, there were appreciably more males than females were on medication. This disparity could be because females are usually less economically empowered than males in the study area  and therefore less able to seek for medical attention compared to their male counterparts.
This study reported higher levels of circulating BDNF in the glaucoma patients compared to the controls. This result contradicts previous studies that reported lower serum BDNF levels in glaucoma patients compared to that of apparently healthy controls.,, The levels of BDNF reported in these studies were related to the stage and severity of the disease. For example, Shpak et al. reported lower levels of BDNF compared to the control in the early stages of POAG and a relative increase of the level in the next stages of the disease. Oddone et al. reported low BDNF values when compared to control in early and moderate glaucoma but not in the advanced disease. Our findings reveal an important role for medication in the dynamics of serum BDNF in the patients. The glaucoma patients on medication in the study had high BDNF levels when compared to healthy controls and naïve patients (patients not yet started on medication). The fact that the naïve glaucoma patients in this study had many times lower BDNF levels when compared to the healthy controls and glaucoma patients on medication indicates that untreated glaucoma presents with low BDNF level which is in agreement with previous reports.,, Coupled with the fact, we have found medication to be a cause of variation in BDNF level and to have a significant association with circulating BDNF levels, it is logical to hypothesize that the high BDNF level in the patients on glaucoma medication could be a result of a rebound increase following commencement of treatment. Damage to the optic nerve and selective death of RGCs, the hallmark of POAG, is due to high IOP.,,,,, Lowering IOP is the major goal of treatment for POAG. It is obvious therefore, to expect major changes in the pathophysiology of the disease due to treatment, including reversal of the BDNF dynamics in the form of rebound increase in BDNF level.
So in essence, we have observed very low serum BDNF among naïve glaucoma patients and a higher than normal serum BDNF among glaucoma patients on medication which we propose to be due to rebound increase. This notion is further supported by another finding of this study that the patients with the worst visual impairment had the lowest levels of BDNF and this finding is consistent with another previous study. This is in line with the fact that glaucoma results from withdrawal of neurotrophins leading to death of RGC's. Research into the actual events leading to the death of RGCs has delineated several mechanisms that may be responsible, including neurotrophin withdrawal due to retrograde axoplasmic transport block, glutamate-induced excitotoxicity, free radical generation, nitric oxide neurotoxicity, and apoptosis. The neurotrophic hypothesis holds that mammalian neuronal growth and maintenance depend on the viability of retrograde axoplasmic transport of soluble growth factors called neurotrophins. Neurotrophins have been implicated in survival and growth promoting activities in the central and peripheral nervous systems in vivo and in vitro. In addition, it has been shown that BDNF also prevents RGC death following optic nerve injury in the cat which has eyes that are comparable in size and vitreal volume to those of primates. A longitudinal study is needed to test our proposed hypothesis. Further studies may prove the potential for circulating BDNF to serve as a therapeutic target and a biomarker to assess the severity of glaucoma or monitor progression of glaucomatous damage or even the efficacy of treatment.
The proportion of the patients on medication to those not medication (about 8:2) and the sociodemographic features of the participants of this study explain the disparity between the results of this study and the previous ones in terms of BDNF findings. Furthermore, difference in the age of the study populations can also be a contributor to differences in circulating BDNF in this study when compared with others. POAG is predominantly a disease of the elderly and is much more common in people aged 35 years and above. Various population-based studies have proven the association between increasing age and an increased risk of the development of POAG., Lommatzsch et al. reported that BDNF level decreased with advancing age, but this report disagrees with the finding of this study, in which no correlation was found between BDNF and age. In addition, advanced age has been reported as a recognized risk factor for POAG., and the fact that the average age above 50 years of the glaucoma patients in this study corroborates this finding.
| Conclusion|| |
It was concluded that the level of circulating BDNF in POAG patients on treatment is high, whereas the level in those not on treatment is low compared to healthy nonglaucoma patients. The level of BDNF is influenced by visual impairment and is associated with coexisting medical conditions in the patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Palimkar A, Khandekar R, Venkataraman V. Prevalence and distribution of glaucoma in central India (Glaucoma survey 2001). Indian J Ophthalmol 2008;56:57-62.
] [Full text]
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis. Ophthalmology 2014;121:2081-90.
Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D. Variations in primary open-angle glaucoma prevalence by age, gender, and race: A Bayesian meta-analysis. Invest Ophthalmol Vis Sci 2006;47:4254-61.
Rabiu MM, Gudlavalleti MV, Gilbert CE, Sivasubramaniam S, Kyari F, Abubakar T. Ecological determinants of blindness in Nigeria: The Nigeria national blindness and visual impairment survey. S Afr Med J 2011;101:53-8.
Kyari F, Abdull MM, Sallo FB, Spry PG, Wormald R, Peto T, et al.
Nigeria normative data for defining glaucoma in prevalence surveys. Ophthalmic Epidemiol 2015;22:98-108.
Tang LL, Sanders R. Pathogenic Mechanisms of Glaucoma. Ichhpujani P, editor. Glaucoma: Basic and Clinical Perspectives. 1st
ed. London: Future Medicine Ltd.; 2013. p. 7-27.
Awoyesuku EA, Fiebai B. Neuroprotection in glaucoma : A review. Niger Health J 2011;11:43-6.
Pan Y, Varma R. Natural history of glaucoma. Indian J Ophthalmol 2011;59 Suppl: S19-23.
Mikelberg FS. Modern concepts of the diagnosis and treatment of chronic open-angle glaucoma. Can Fam Physician 1986;32:1500-4.
Chader GJ. Advances in glaucoma treatment and management: Neurotrophic agents. Invest Ophthalmol Vis Sci 2012;53:2501-5.
Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA, Zack DJ. Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci 2000;41:764-74.
Kragha IK. Prevalence of glaucoma in an eye hospital in Nigeria. Am J Optom Physiol Opt 1987;64:617-20.
Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, et al.
Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 2011;14:347-53.
Ghaffariyeh A, Honarpisheh N, Heidari MH, Puyan S, Abasov F. Brain-derived neurotrophic factor as a biomarker in primary open-angle glaucoma. Optom Vis Sci 2011;88:80-5.
World Medical Association. World medical association declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 2013;310:2191-4.
Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90:262-7.
Chang LC, Teng MC, Chang HW, Lai IC, Lin PW, Tsai JC, et al.
The probability of blindness in patients treated for glaucoma. Chang Gung Med J 2005;28:492-7.
James D, Yim L. Risk factors for glaucoma. J Geriat Med 2007;4:43-8.
Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol 2008;53 Suppl 1:S3-10.
Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. Arch Ophthalmol 1998;116:1640-5.
Sommer A. Glaucoma risk factors observed in the baltimore eye survey. Curr Opin Ophthalmol 1996;7:93-8.
Acha KC. Trend and levels of women empowerment in Nigeria. Am J Appl Math Stat 2014;2:402-8.
Oddone F, Roberti G, Micera A, Busanello A, Bonini S, Quaranta L, et al.
Exploring serum levels of brain derived neurotrophic factor and nerve growth factor across glaucoma stages. PLoS One 2017;12:e0168565.
Shpak AA, Guekht AB, Druzhkova TA, Kozlova KI, Gulyaeva NV. Brain-derived neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract. Curr Eye Res 2018;43:224-31.
Gupta V, You Y, Li J, Gupta V, Golzan M, Klistorner A, et al.
BDNF impairment is associated with age-related changes in the inner retina and exacerbates experimental glaucoma. Biochim Biophys Acta 2014;1842:1567-78.
Domenici L, Origlia N, Falsini B, Cerri E, Barloscio D, Fabiani C, et al.
Rescue of retinal function by BDNF in a mouse model of glaucoma. PLoS One 2014;9:e115579.
Kimura A, Namekata K, Guo X, Harada C, Harada T. Neuroprotection, growth factors and BDNF-TrkB signalling in retinal degeneration. Int J Mol Sci 2016;17. pii: E1584.
Feng L, Chen H, Yi J, Troy JB, Zhang HF, Liu X. Long-term protection of retinal ganglion cells and visual function by brain-derived neurotrophic factor in mice with ocular hypertension. Invest Ophthalmol Vis Sci 2016;57:3793-802.
Mysona BA, Zhao J, Bollinger KE. Role of BDNF/TrkB pathway in the visual system: Therapeutic implications for glaucoma. Expert Rev Ophthalmol 2017;12:69-81.
Paula JS, Furtado JM, Santos AS, Coelho Rde M, Rocha EM, Rodrigues Mde L, et al.
Risk factors for blindness in patients with open-angle glaucoma followed-up for at least 15 years. Arq Bras Oftalmol 2012;75:243-6.
Ko ML, Hu DN, Ritch R, Sharma SC. The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma. Invest Ophthalmol Vis Sci 2000;41:2967-71.
Weber AJ, Harman CD. BDNF preserves the dendritic morphology of alpha and beta ganglion cells in the cat retina after optic nerve injury. Invest Ophthalmol Vis Sci 2008;49:2456-63.
Mitchell P, Hourihan F, Sandbach J, Wang JJ. The relationship between glaucoma and myopia: The blue mountains eye study. Ophthalmology 1999;106:2010-5.
Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, et al.
The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 2005;26:115-23.
[Table 1], [Table 2], [Table 3]