Relationship Between Brain-Derived Neurotrophic Factor and Cognitive Function in Methamphetamine-Dependent Patients
Article information
Abstract
Objective
Methamphetamine (METH) is a neurotoxic substance that can induce neurodegeneration in the human brain. Consequently chronic METH use can affect the cognitive functions in METH-dependent patients. In this study, we aimed to identify the relationship between cognitive function and brain-derived neurotrophic factor (BDNF), which reflects the status of neuroadaptive changes, by characterizing the effects on the cognitive function of METH-dependent patients.
Methods
A total of 38 METH-dependent patients participated in this study. BDNF levels were measured using the enzyme-linked immunosorbent assay. We also examined the clinical features based on the measurements of the Consortium to Establish a Registry for Alzheimer’s Disease-Korean version (CERAD-K). Finally, the relationships between various parts of CERAD-K and BDNF were compared with one another.
Results
METH-dependent patients were able to conduct most parts of CERAD-K stably. Among the parts of CERAD-K, only trail-making test part B was correlated with BDNF.
Conclusion
The trail-making test is specific for evaluating executive function; therefore, BDNF may play an essential role in detecting neurocognitive functional decline in METH dependence.
INTRODUCTION
Methamphetamine (METH) is a psychostimulant that acts on the central nervous system. METH addiction is known to cause serious socioeconomic problems and medical issues to its users [1].
METH is a neurotoxic substance; therefore, its dependence results in various neurodegenerative issues, including cognitive impairment [2,3]. Furthermore, METH can cause neuronal damage, facilitate neurodegeneration, and trigger apoptosis. Several mechanisms of neurodegeneration are found to be associated with METH usage [4]. First, METH can increase the release of monoamines into the synaptic vesicles. Excessive dopamine released by chronic METH usage can lead to the excitation of the dopaminergic neurons, which can consequently induce neurotoxicity. Second, the neurotoxicity caused by METH use can activate glutamatergic transmission. The accumulation of glutamate in the synapse increases intracellular calcium influx, and activates enzymes, such as nitric oxide, by mediating the excess calcium concentration. This ultimately results in nerve damage. Additionally, neuroinflammation can be caused by inflammatory cytokines activated by METH. Also, oxidative stress and free radicals contribute to degenerative changes in the neuronal membrane by triggering apoptosis.
METH-induced nerve structure changes in the brain are observed throughout the brain region, indicated by degeneration of the cingulate and limbic areas and reduction of the hippocampus volume [5,6]. Since the hippocampus plays an essential role in memory and cognitive functions. A marked clinical symptom related to brain nerve damage in METH dependence is cognitive impairment [7]. Long-term use of METH can lead to the development of cognitive impairment [8]. Chronic METH use can cause temporary cognitive impairment as well as permanent structural damage in the brain [9,10]. METH-dependent patients have been reported to have inferior cognitive functions related to learning and memorization. Moreover, psychomotor delay and decrease in attention have also been reported [11]. Notably, chronic METH use can cause a decrease in executive functions related to attention, problem-solving skills, and self-control [12-14]. These disorders can be the main factor for adverse prognosis by limiting patients’ social adaptation and rehabilitation functions.
Neurotrophins consist of polypeptides that are primarily distributed in the nervous system. They are involved in the activation, differentiation, and survival of the brain’s nerve cells [15,16]. Brain-derived neurotrophic factor (BDNF) is a typical neurotrophin involved in neuronal growth, differentiation, synaptic connection, modification, and survival [17]. Previous studies have identified the relationship between BDNF and mental illnesses, including depression and schizophrenia [18]. A study reported lower BDNF levels in patients with depression compared to controls [19]. Additionally, the study confirmed reduced volume of the limbic brain system, including the hippocampus, in patients with depression. Considering that depression is associated with decreases in neurogenesis and various neuro-factors [20], a decline in BDNF levels in depressed patients may reflect such neurodegeneration. In a study on BDNF levels in substance addiction, i.e., alcohol dependence, BDNF level was lower in patients with alcohol dependence than in controls [21]. The authors of that study argued that BDNF could serve as a neurotoxicity index subject to alcohol, as it is involved in neuronal survival and may indicate resistance against neuronal degeneration. In another relevant study, blockade of N-methyl-D-aspartate receptors due to alcohol was reported to reduce BDNF expression, thereby increasing neurotoxicity [22]. Additionally, heroin is known to cause neurodegeneration. Serum BDNF levels were decreased in long-term heroin users [23].
BDNF has been known as a potential indicator for cognitive function decline accompanied by mental disorders. In patients with schizophrenia, BDNF has been associated with verbal walking memory and other negative symptoms [24]. BDNF was also shown to be related to cognitive functions in patients with depression [25]. Some researchers asserted that BDNF can be a potential physiological index to signal memory decline and general cognition in the aging process [26].
In case of alcohol dependence, cognitive functions can be measured using neurocognitive tests such as the Wechsler Memory Scale and Wisconsin Card Sorting Test, or categories subset of Halstead-Reitan Neuropsychological Test Battery [27,28]. Other studies have used the trail-making test [29], or Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) for cognitive function evaluation of alcohol-dependent patients [30].
To date, no study has investigated a direct relationship between BDNF and cognitive functions of METH-dependent patients. A previous study has reported on the role of BDNF gene polymorphism in cognitive functions in METH patients, in which the potential of BDNF as a biomarker of cognitive function of METH patients was suggested [31]. In another study, the levels of serum proteins regulating the BDNF signaling pathway were measured in accordance to the Montreal Cognitive Assessment screening tool for the evaluation of BDNF and cognitive function in METH patients [32]. As these studies show, BDNF, the neurotrophin, holds great potential as an index for reflecting the cognitive functional status of METH-dependent patients
The present study aimed to evaluate the cognitive functions of METH-dependent patients to determine the relationship between BDNF and cognitive functions of METH-dependent patients. Furthermore, we measured BDNF levels and performed correlational analysis to investigate the potential use of BDNF as a neuro-factor reflecting the functional status of METH-dependent patients’ cognition.
METHODS
Research participants
A total of 38 male patients undergoing treatment at the Gangnam Eulji Hospital outpatient department participated in this study. Patients were diagnosed with METH dependence by a psychiatrist, following the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria. All participants were aged 25–71 years. Patients with addiction to other substances than METH were excluded, as were those with a history of severe head trauma or dementia. A minimum of 8 weeks of agent cessation was confirmed in the patients via a drug reaction test.
The demographic and clinical characteristics of the research participants are presented in Table 1. The study was approved by the clinical trial review committee at the Eulji University approved the study (EUIRB2018-122). All research participants signed the consent form after receiving explanations about this study’s goal directly by the researcher.
Demographic characteristics of patients and METH userelated data
Measurement
A survey questionnaire was used for all participants to investigate demographical variables such as age, education, age at drug use initiation, and the total duration of drug use. Cognitive function was evaluated using the CERAD-Korean version (CERAD-K) [3].3 These neuropsychology tests consist of nine test items to assess parameters such as linguistic abilities, memory skills, compositional skills, and executive function [34].
Blood analysis
Blood samples of all participants were obtained by a nurse between 10:00 AM and 11:00 AM. Ten mL of blood were added to a serum separator tube and was allowed to clot for 30 minutes at room temperature before being centrifuged for 15 minutes at 1,000×g. Then serum samples were extracted and stored at ≤-20°C. BDNF was measured using the Human Magnetic Luminex assay kits (LXSAHM-01) (R&D Systems). The experiment was conducted following manufacturer’s instructions. The serum samples were diluted 1:50 in assay buffer. Fifty microliters of the microparticle cocktail were added to each well of the plate, followed by the addition of 50 μL of the diluted sample to each well. After incubating at room temperature for 2 hours, the liquid was removed using a magnet to pull the particles to the bottom of the plate. Each well was then washed with 100 μL of wash buffer, and this washing step was repeated three times to ensure complete removal of the liquid. Next, 50 μL of the diluted biotin-antibody cocktail was added to each well, and the plate was sealed with a foil plate sealer. The plate was incubated at room temperature for 1 hour on a shaker set to 800 rpm. Following this, 50 μL of streptavidin-phycoerythrin was added to each well, and the plate was resealed with the foil plate sealer. The plate was incubated at room temperature for 30 minutes on the shaker at 800 rpm. After three additional washes with 100 μL of wash buffer, another 100 μL of wash buffer was added to each well. Finally, the absorbance was measured using the Luminex 200 (EMD Millipore).
Statistical analysis
A descriptive statistical analysis of demographic variables, such as age, education, age at drug use initiation, a total duration of drug use and total abstinence periods, was conducted for METH-dependent patients.
We performed Kolmogorov–Smirnov test and Shapiro–Wilk test to check the normality of the data. And we used Pearson correlation coefficient and linear regression analysis to determine the correlation between demographic data and neuropsychological test results from the CERAD-K and BDNF serum levels. Statistical analysis was performed using the Statistical Package for Social Sciences-18, windows version (SPSS Inc.). Statistical significance was determined by p<0.01 for all analyses.
RESULTS
Characteristics of demographic variables and METH dependence problems
Age, education, age at drug use initiation, and the total duration of drug use of all participants are presented in Table 1. The average values of participants’ age and education were approximately 48 years and 10 years, respectively. The average age at initiation of METH use was 29.8 years. These data revealed no correlation between serum BDNF levels and the CERAD-K.
Relationship between METH dependence and neurocognitive functions
METH-dependent patients in this experiment demonstrated a relatively stable ability to perform most of the subitems of the CERAD-K (Table 2).
Results of CERAD-K
Relationship between BDNF and neurocognitive function of METH-dependent patients
To evaluate the normality of variables, we present a normal probability plot to visually check the normality of the serum BDNF level (Figure 1). In the figure, the serum BDNF level are generally located close to the diagonal line, suggesting normality. Among the the sub-items of the CERAD-K, the trail-making test part B (TMT-B) was correlated with BDNF (r=0.407, p<0.01) (Table 3).
Normal probability-probability plot of regression analysis. BDNF, brain-derived neurotrophic factor.
Correlations between BDNF, TMT-A, and TMT-B
DISCUSSION
The goal of the present study was to investigate the relationship of BDNF with the cognitive function of METH-dependent patients. A correlation analysis between the CERAD-K results and BDNF in METH-dependent patients revealed that METH-dependent patients had relatively stable executive functions for most CERAD-K items. No apparent correlation was found between BDNF and most CERAD-K items, except that the trail-making tests (e.g., TMT-B) was correlated with BDNF. To date, not many studies have reported on the correlation of neurotrophin with the cognitive function of METH-dependent patients; this study’s findings are notable in that they suggest the potential of BDNF for reflecting the cognitive function of METH-dependent patients.
The trail-making test is a neurocognitive functional measurement tool commonly administered to assess the degree of brain damage and known to measure psychomotor speed and attention [35]. Remarkably, it can also measure executive function. It involves complex visual scanning and kinetic factors to evaluate visual-motor tracking and is associated with factors such as attention span-persistence and psychomotor speed. Trail making test part A (TMT-A) is less affected by education and intellectual capability than TMT-B [36]. TMT-A is sometimes used for cognitive psychological tests to evaluate poor education or executive cognitive function, whereas TMT-B requires that alternating numbers and characters be connected and takes longer to administer than TMT-A. TMT-B requires increased motor speed and visual exploration. Therefore, it involves a complicated cognitive process and is affected more by acquired learning ability, such as the education level [37]. This study found that BDNF level was positively correlated with TMT-B in METH-dependent patients and related to their executive functions. In other words, the BDNF level was higher in patients with lower executive function, which is in agreement with the research finding that the BDNF concentrations of METH users were significantly higher compared to those of normal controls [38]. The authors of this study insisted that the elevation of BDNF level of METH users could be the representation of a neuroadaptation to METH induced toxicity. Therefore, they suggested that BDNF can play some role in adaptation to the neurotoxicity of METH.
In a study that investigated the correlation between BDNF and cognitive function in patients with depression, the TMT-B involving various neurocognitive tests was correlated with cognitive function, although that study was not about METH-dependent patients [25]. This study confirmed cognitive function decline in patients with depression compared to normal controls. Moreover, the linear regression analysis revealed a negative correlation between BDNF and TMT-B.
Various studies have reported the correlation between BDNF and mental illnesses, but no clear relationship has been established. Also, measurement results vary depending on whether it was made from a serum sample or plasma sample [39]. Unlike diseases reflecting chronic neurodegenerative state, such as depression, METH dependence is highly likely to modify physical conditions due to drug use factors, e.g., the period of drug cessation and the period of drug use. Various neurological changes can be induced in a hyper-excitable response state, such as the METH withdrawal state. Serum BDNF level was elevated in METH-dependent patients [38]. In this study, the increase in BDNF levels was considered to be caused by a neuroadaptive process for METH neurotoxicity.
Although METH is neurotoxic, neurodegeneration or cognitive deficit occurring in the patients may produce different outcomes depending on the state of intoxication or when the withdrawal symptoms occur. Additionally, after the patients stop taking the drug, some impairment may be reversible and may even improve, while others may leave irreversible impairments. This study found a significant correlation only for the trail-making tests but not for the remaining variables. This may be due to the partially impaired cognitive function of METH-dependent patients. A recent study found that impaired executive functioning significantly affects the development and persistence of substance addition [40], which is consistent with our study’s findings. Future studies are warranted to report the relationship between METH dependence and neurotrophin and the mechanisms of cognitive function deficit with neurotrophin involvement in METH-dependent patients.
Notably, cognitive impairment can persist in some patients, even if a significant length of time has passed. Such disorders influence the treatment effect and post-treatment adaptation to life for the patient. The mechanism of this cognitive defect in METH-dependent patients are various
The present study has several limitations.
First, all participants were male, the sample size was relatively small. And cognitive function differences between METH-dependent patients and healthy controls were not directly compared. Second, we collected serum BDNF levels with a blood test. But some studies measured the BDNF levels with a cerebrospinal fluid test. This method may be more direct to measure BDNF levels and often useful for the dementia study. Third, this study used CERAD to evaluate the cognitive function of patients. CERAD is a measurement tool of neurocognitive degeneration, typically used for diseases accompanied by the aging process, so it may not be the most suitable tool to determine the cognitive function of METH-dependent patients. Future studies that combine brain imaging and other psychological assessments could yield clearer results.
Despite these limitations, we found that BDNF may serve as a potential indicator of cognitive impairment in METH-dependent patients. This study demonstrates that METH can affect the cognitive function of patients, highlighting its neurological risks. The findings of this study will contribute to raising awareness in clinical and public health fields about the dangers of METH abuse as an illegal drug.
In, conclusion, the present study found a correlation between BDNF, a neurotrophin, and the TMT-B that reflects executive function, in METH-dependent patients. BDNF is a protective factor against neurodegeneration due to METH, and this study suggests its potential to serve as a physiological index reflecting the nerve regeneration in METH patients. Further studies are necessary to identify the correlation between neurotrophin and BDNF activity and pathologies that reduce cognitive function in METH-dependent patients.
Notes
Availability of Data and Material
The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.
Conflicts of Interest
The authors have no potential conflicts of interest to disclose.
Author Contributions
Conceptualization: Hwallip Bae, Changwoo Han. Data curation: Changwoo Han. Formal analysis: Sung-Doo Won. Funding acquisition: Changwoo Han. Investigation: Changwoo Han. Methodology: Sung-Doo Won, Changwoo Han. Project administration: Jiyoun Kim, Hye-Jin Seo. Resources: Jiyoun Kim, Hye-Jin Seo. Software: Sung-Doo Won. Supervision: Jiyoun Kim, Hye-Jin Seo. Validation: Changwoo Han. Visualization: Changwoo Han. Writing—original draft: Hwallip Bae, Changwoo Han. Writing—review & editing: Hwallip Bae, Changwoo Han.
Funding Statement
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07047505).
Acknowledgements
None