Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue Syndrome and Multiple Sclerosis

Abstract

Objective: This study examined the levels of a major regulator of neuronal survival, brain derived neurotrophic factor (BDNF) in two populations: individuals with multiple sclerosis and chronic fatigue syndrome. BDNF is a protein involved in the maintenance and maturation of both peripheral and central neurons. In patients with multiple sclerosis, BDNF expression is often decreased and believed to reflect ineffective repair mechanisms. As a preliminary exploration, we examined the production of BDNF on the part of peripheral blood mononuclear cells in three groups: patients with Chronic Fatigue Syndrome (CFS [n=15]), patients with multiple sclerosis (n=57), and a set of putatively healthy controls (n=37).
Methods: Mononuclear cells were extracted from peripheral blood samples and cultured for 48 hours. Production of BDNF was evaluated from phyto-haemagglutinin (PHA) and phorbol-12-myristate-13-acetate (PMA) stimulated and unstimulated cells. BDNF levels were determined using a commercially available enzyme linked immunoabsorbent assay (sensitivity: 62.5-4,000 pg/mL).
Results: Both CFS and MS samples displayed nearly identical levels of BDNF, levels that were 25 percent of that displayed by the healthy control sample. For unstimulated cells, the BDNF values were 404.71 pg/ml for the CFS sample, 573.33 pg/ml for the MS sample and 1,114.15 pg/ml for the control sample. For stimulated cells, the BDNF values were 442.55 pg/ml for the CFS sample, 367.33 pg/ml for the stimulated MS sample, and 1432.24 pg/ml for the stimulated control sample.
Conclusion: The decreased production of BDNF on the part of MS patients is consistent with the literature.
However, the decreased production in those with CFS was unexpected and a novel finding. This finding could reflect a reduced ability to maintain neuronal structure and function in those with CFS. Future studies are needed to evaluate for neuronal damage in those with CFS

Full text

Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue Syndrome
and Multiple Sclerosis
Matthew Sorenson1*, Leonard Jason2, Jonna Peterson3, Joshua Herrington4, and Herbert Mathews5
1School of Nursing, De Paul University, Chicago, USA
2Department of Psychology, De Paul University, Chicago, USA
3Rush University, Chicago, USA
4Florida International University, Florida, USA
5Loyola University Chicago, Chicago, USA
*Corresponding author: Matthew Sorenson, Associate Professor/Associate Director DePaul University School of Nursing, 990 West Fullerton Ave., Suite 3000,
Chicago, IL. 60614, USA, Tel: 773-325-1887; Fax: 773-325-7282; E-mail: msorenso@depaul.edu
Received date: Mar 2, 2014, Accepted date: Apr 25, 2014, Published date: Apr 30, 2014
Copyright: © 2014 Sorenson M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Objective: This study examined the levels of a major regulator of neuronal survival, brain derived neurotrophic
factor (BDNF) in two populations: individuals with multiple sclerosis and chronic fatigue syndrome. BDNF is a protein
involved in the maintenance and maturation of both peripheral and central neurons. In patients with multiple
sclerosis, BDNF expression is often decreased and believed to reflect ineffective repair mechanisms. As a
preliminary exploration, we examined the production of BDNF on the part of peripheral blood mononuclear cells in
three groups: patients with Chronic Fatigue Syndrome (CFS [n=15]), patients with multiple sclerosis (n=57), and a
set of putatively healthy controls (n=37).
Methods: Mononuclear cells were extracted from peripheral blood samples and cultured for 48 hours. Production
of BDNF was evaluated from phyto-haemagglutinin (PHA) and phorbol-12-myristate-13-acetate (PMA) stimulated
and unstimulated cells. BDNF levels were determined using a commercially available enzyme linked immuno
absorbent assay (sensitivity: 62.5-4,000 pg/mL).
Results: Both CFS and MS samples displayed nearly identical levels of BDNF, levels that were 25 percent of that
displayed by the healthy control sample. For unstimulated cells, the BDNF values were 404.71 pg/ml for the CFS
sample, 573.33 pg/ml for the MS sample and 1,114.15 pg/ml for the control sample. For stimulated cells, the BDNF
values were 442.55 pg/ml for the CFS sample, 367.33 pg/ml for the stimulated MS sample, and 1432.24 pg/ml for
the stimulated control sample.
Conclusion: The decreased production of BDNF on the part of MS patients is consistent with the literature.
However, the decreased production in those with CFS was unexpected and a novel finding. This finding could reflect
a reduced ability to maintain neuronal structure and function in those with CFS. Future studies are needed to
evaluate for neuronal damage in those with CFS.
Keywords: Chronic fatigue syndrome; Multiple sclerosis; BDNF;
Nerve growth factors; Neutrophic protein
Introduction
Chronic Fatigue Syndrome (CFS) affects approximately one million
Americans, at a cost of billions of dollars to the economy [1].
Emerging evidence suggests the immune system is involved in the
pathogenic process of chronic fatigue syndrome [2-5]. While many
studies have attempted to clarify the role of the immune system in
CFS, little has been accomplished in terms of developing a consensus
opinion as to the precise nature of immunologic dysfunction. Immune
abnormalities such as low Natural Killer (NK) cell count and
dysfunction, along with an imbalance in type I and type II immune
response have been suggested, however a great deal of heterogeneity
still exists within the CFS literature [6-8]. A guide to future research
may be found in work done with Multiple Sclerosis (MS), a neurologic
condition in which fatigue is the most common symptom and one that
may share some etiologic similarity with CFS [9].
Multiple Sclerosis is a chronic, degenerative neurologic disorder
evolving from progressive destruction of the myelin sheath, resulting
in a loss of nerve propagation. The destruction of myelin occurs as the
result of an autoimmune process in which immune components attack
myelin in the central nervous system [10]. The initiation and
perpetuation of this pathogenic process is believed mediated by
disruptions in the production of certain immune proteins known as
cytokines. Of particular note is that the most common symptom
displayed by those with MS, is fatigue [11]; a pronounced sense of
fatigue that can have pervasive effects on quality of life and functional
ability. MS-related fatigue is the leading contributing factor to
disability with independent adverse effects on quality of life [12].
While the prevalence of fatigue and its effects on activities of daily
living in the MS population are well documented, the causative
mechanisms underlying fatigue remain unclear.
Neurology & Neurophysiology
Sorenson et al., J Neurol Neurophysiol 2014,
S12:013
http://dx.doi.org/10.4172/2155-9562.S12-013
Research Article Open Access
J Neurol Neurophysiol Neurodegenerative Diseases: Symptoms and
Therapeutics
ISSN:2155-9562 JNN, an open access journal

Several potential mechanisms may underlie MS-related fatigue.
States of psychological distress/stress have been found associated with
fatigue with evidence pointing to the possibility of shared causative
pathways [13,14]. Heightened psychological stress may be associated
with the expression of pro-inflammatory cytokines that are also
correlated with fatigue and disease symptomatology. For example, the
expression of messenger RNA for the pro-inflammatory cytokine
tumor necrosis factor alpha (TNF- α) has been found associated with
fatigue in individuals with MS [15] as well as with perceived stress.
This cytokine working in conjunction with interferon-gamma (IFN-γ)
is believed to be one of the operative players in the demyelinative
process. While psychological variables may contribute to fatigue
through mediation of immune function, it is just as possible that
increasing disease symptomatology could affect ambulative and
functional ability with end effects on fatigue. Although, clinical
experiences on the part of the lead author have revealed that while
patients with MS report significant fatigue, strength and reflex testing
during the neurologic examination often evidences no apparent
deficit. There may be pathogenic mechanisms leading to fatigue that
are distinct from those mechanisms affecting physical mobility. In
turn, the administration of immunomodulatory agents during the
treatment course can induce a pronounced sense of fatigue; most likely
through modulation of cytokine production. It then appears that
fatigue is at the very least, mediated by immunologic function.
Recently, evidence has emerged demonstrating close associations
between MS and CFS in terms of potential immunologic mechanisms
and symptom clusters [9]. Other findings have demonstrated the
presence of small white matter hyper intensities in the frontal lobes of
a subset of patients with CFS [16]. The presence of such lesions implies
the potential presence of immunologic dysfunction within the central
nervous system of those with CFS, perhaps similar to that found in
MS. In order to investigate the possibility of shared pathogenic
markers, this study examined brain derived neurotrophic factor in
those with MS and CFS.
Brain Derived Neurotropic Factor (BDNF) is a versatile protein,
classified as a member of the neurotrophin family of growth factors,
and is found throughout the central nervous system (CNS). It plays a
primary role in the formation of the developing nervous system, and
contributes to neural plasticity through adulthood. BDNF protein
expression has been associated with neural regeneration throughout
the body; indeed it is usually found wherever innervations are present.
An early animal study found evidence for widespread immuno-
activation of BDNF mRNA transcription in the central nervous system
(CNS), with concentrations in the lateral septum, bed nucleus of the
stria teminalis, medial preoptic nucleus, olivery pretectal nucleus,
lateral paragigan to cellular nucleus and the dorsal horn of the spinal
cord in adult rats [17].
BDNF is also produced by cells of the immune system. It is secreted
by Th1 and Th2 lymphocytes and macrophages, and aids in the
growth of cells that may have become damaged by physical injury or
neurotropic pathogens. High levels of circulating cytokines in the
blood, as in the case of some patients with MS, are known to affect
circulating levels of BNDF [18]. This protein is a major component of
the neurotrophic theory of depression [19]. The down-regulation of
BDNF has been found to lead to neuronal atrophy within the
hippocampus, a finding that aids in explaining stress-induced
depression [20].
Recently, researchers have focused their attention on the potential
of therapeutic and diagnostic uses of BDNF, sometimes with
conflicting results. A study that focused on neural plasticity in adult
mouse models associated low levels of BDNF with the development of
depression [21]. A more recent cohort study examining the genetic
component of BDNF reported findings that did not indicate a major
influence in the development of depression [22]. Data from a study
examining neural lesions in patients with multiple sclerosis (MS)
reported that the concentration of BDNF immuno-positive cells were
positively correlated with demyelinating activity at lesion sites in the
central nervous system [23]. Also, brain derived neurotrophic factor
(BDNF) has been shown to be sensitive to exercise in both animal [24]
and human populations [25]. So far, very little research has been
conducted to examine the role of BDNF in CFS. A literature review
yielded only one study [26] that observed an increase of BDNF after an
exercise induced state of fatigue in mice. So far, no single clinical
standard or diagnostic tool has become available for this debilitating
disease. Considering the potential shared immunologic mechanisms
between MS and CFS, the study sought to determine the level of BDNF
in these disease states in comparison with controls.
Method
A total of 109 participants (Mean age =40.5, SD =13.9) participated
in the study. Three separate subgroups were included; 15 participants
who met diagnostic criteria for CFS, 57 participants meeting the
McDonald criteria for MS [27], and 37 putatively healthy participants
who served as controls. Participants with CFS were recruited from a
list of individuals who had previously participated in an
epidemiological study on CFS. All participants with CFS were
positively identified as meeting criteria for CFS [1] and were diagnosed
by a physician. All persons involved in the research study were at least
18 years of age, not pregnant, able to speak English, and physically and
willfully able to travel to the research center.
All patients with CFS in this study were screened by a licensed
physician. Medical examinations included general neurological and
physical assessments, as well as a more in-depth evaluation of medical
and neurological history. These measures were intended to assess the
symptoms, and medical history, of those with CFS in order to rule out
any co-occurring medical conditions. Additional medical information
deemed relevant to the study was collected to avoid medical confounds
for CFS diagnosis, including exposure to HIV/AIDS, tuberculosis, and
other non HIV/AIDS sexually transmitted diseases. Information on
prescribed and illicit drug use was also assessed and recorded. A
history of CFS symptoms was reported as a final measure. Laboratory
tests included a complete blood cell count with differential and platelet
count, chemistry screen (which assesses thyroid, renal, and liver
functioning), Hepatitis B, Lyme disease screen, erythrocyte
sedimentation rate, arthritic profile (which includes rheumatoid factor
and an-ti-nuclear antibody), HIV screen and urinalysis. A tuberculin
skin test was also performed. The project physician performed a
detailed medical examination to detect evidence of diffuse cardiac or
pulmonary dysfunction, adenopathy, synovitis, neuropathy,
myopathy, or hepatosplenomegaly.
A convenience sample of male and female patients diagnosed with
MS was recruited from two outpatient neurology clinics. Subjects
treated with natalizumab, mitoxantrone or taking oral contraceptives
were excluded as were those receiving other immunomodulatory
therapies. All subjects were free of steroidal or other
immunosuppressant therapy for at least two months prior to
enrollment. Also excluded were subjects with current symptoms of
Citation: Sorenson M, Jason L, Peterson J, Herrington J, Mathews H (2014) Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue
Syndrome and Multiple Sclerosis. J Neurol Neurophysiol S12: S2-013. doi:10.4172/2155-9562.S12-013
Page 2 of 6
J Neurol Neurophysiol Neurodegenerative Diseases: Symptoms and
Therapeutics
ISSN:2155-9562 JNN, an open access journal

cardiovascular, respiratory, or neoplastic disease, pregnancy, or non-
MS autoimmune disorders.
A control group (n=37) that was age and gender range (Mean age
43.5, SD=2.56) matched to the MS sample population was recruited as
part of a separate investigation. The control sample was comprised of
healthy individuals with no history of significant illness or injury. All
control subjects were free of current symptoms of cardiovascular,
respiratory, neoplastic or other autoimmune disorders. The study was
approved by the Institutional Review Boards of Loyola University
Medical Center, DePaul University and Edward Hines Jr. VA Hospital.
Peripheral blood collection
Peripheral blood was drawn into lithium citrate tubes and
processed within six to eight hours of sample procurement. Plasma
samples were obtained from blood collection tubes which were spun
for 20 minutes at 1000 X g, and plasma aliquots were pipetted directly
from each tube with Phosphate Buffered Saline used for volume
replacement. Afterward heparinized peripheral blood was overlaid
onto Ficoll/Hypaque and then centrifuged at 1000 X g for 20 min.
Cells at the interface were washed with Hank's Balanced Salt Solution
(HBSS) and enumerated with a standard hemacytometer.
PBMC’s (1 x 106) were cultured in RPMI 1640 plus 10% fetal
bovine serum (supplemented with glutamine, penicillin,
streptomycin), with (stimulated) and without (constitutive) a mixture
of phyto-haemagglutinin (PHA) and phorbol-12-myristate-13-acetate
(PMA) (PMA @ 20 ng/well; PHA @ 0.05%/well) in 24 well plates for
48 hr at 370C. After 48 hours, aliquots of supernatant fluid were
collected and stored (-70oC) until analyzed. BDNF levels were
determined using commercially available kits purchased from R&D
Systems (Minneapolis, MN).
Data analysis
All data were initially screened and analyzed descriptively.
Demographic (age, gender) and clinical variables were analyzed to
determine possible independent effects of these variables on immune
profiles. All data were coded and entered into a spreadsheet workbook
created in Microsoft Excel; data were also entered in SPSS Version 18.
Data entries were compared between Microsoft Excel and SPSS to
ensure correct entry. All data analyses were conducted using SPSS
Version 18. The alpha level determined prior to analysis was p=0.05.
All data prior to the conduction of the analysis were examined for the
presence of outliers. In general, an outlier was considered to be a value
that lay outside two standard deviations from the mean. Any such
outlying values were excluded from analysis. A mixed ANOVA was
performed to examine for differences between cell conditions and
subject groups. For all statistical analyses performed; Levine’s test for
equality of variance was applied prior to conduction of t-tests for
independent samples. To compare the production between groups,
serial t-tests for independent samples were performed with the
Bonferroni correction.
Results
Mixed effect analysis
Using mixed ANOVA analysis, there was no significant constitutive
(unstimulated)/stimulated effect [F(1, 106) =2.34, p=.13, partial ηp2
= .02]. However, there were both significant condition [F (2, 106) =
23.04, p < .00, partial ηp2 = .30] and interaction [F (2,106) =35.7, p < .
00, partial ηp2=.40] effects. For the stimulated condition, the control
group was significantly higher than the CFS [t (106) = 4.97, p<.001]
and MS [t (106) = 7.76, p<.001] groups; however, there were no
significant difference for the CFS and MS groups [t (106 =0.40, p=.69].
Level of Constitutive (Unstimulated) PBMC production of
BDNF
The mean level of BDNF produced by PBMC placed in cell culture
for 48 hours (unstimulated) and derived from subjects with CFS was
404.71 pg/ml (SD=313.02). The level for subjects with MS was slightly
higher with a mean of 573.33 pg/ml (SD = 405.81). These mean values
were 25 percent of the level of BDNF produced by control subjects (M
= 1114.15 pg/ml, SD = 808.66) (Figure 1). Control group levels were
significantly higher than the CFS [t (106) = 4.08, p<.001] and MS [t
(106) = 4.5, p<.001] groups; however, there were no significant
difference between the CFS and MS groups, t (106) = 1.02, p=.31.
Citation: Sorenson M, Jason L, Peterson J, Herrington J, Mathews H (2014) Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue
Syndrome and Multiple Sclerosis. J Neurol Neurophysiol S12: S2-013. doi:10.4172/2155-9562.S12-013
Page 3 of 6
J Neurol Neurophysiol Neurodegenerative Diseases: Symptoms and
Therapeutics
ISSN:2155-9562 JNN, an open access journal

Figure 1. Control group levels
Level of Stimulated PBMC production of BDNF
The mean level of BDNF produced by PBMC placed in cell culture
for 48 hours and stimulated with PMA/PHA for those with CFS was
442.55 pg/ml (SD = 323.39), which was slightly greater than levels
produced constitutively. For the MS sample, the mean level of BDNF
was 367.33 pg/ml (SD= 241.87), which was significantly less than that
produced constitutively [t (106) =5.29, p<.001]. Stimulated PBMC
derived from the control group produced a significantly higher mean
level of BDNF (1432.24 pg/ml, SD = 1054.99) than the unstimulated
condition [t (106) =6.58, p<.001]. In the CFS sample, there were no
significant differences between the stimulated and constitutive
conditions [t (106) =0.50, p=.62].
Discussion
These results demonstrate PBMC from patients with CFS or MS
produce similar levels of BDNF, and these levels are significantly less
than that of healthy control subject PBMC. Lower levels of BDNF have
been found in other MS samples [23,28]. However this study is the
first to find comparable lower levels among patients with CFS.
In those with MS, fatigue has been found associated with brain
lesion. Overall measurements of brain lesion (load) are correlated with
fatigue scores with lesions in particular being found in the frontal and
parietal regions of the brain [29]. Interestingly, these areas are also
found to exhibit lesions in select individuals with CFS [16] and are
regions of the brain associated with cognitive function. Not only do
patients with MS and CFS share fatigue as a leading symptom, there
are often cognitive deficits associated with each condition.
In a population experiencing work associated burnout, serum levels
of BDNF were found to be significantly lower than those of a healthy
control comparison group. In that study, no differences were found in
terms of cortisol levels using a suppression test. It is then possible that
low levels of BDNF may be associated with symptoms of altered mood
and cognitive function [30].
Citation: Sorenson M, Jason L, Peterson J, Herrington J, Mathews H (2014) Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue
Syndrome and Multiple Sclerosis. J Neurol Neurophysiol S12: S2-013. doi:10.4172/2155-9562.S12-013
Page 4 of 6
J Neurol Neurophysiol Neurodegenerative Diseases: Symptoms and
Therapeutics
ISSN:2155-9562 JNN, an open access journal

In a murine model of CFS, decreased expression of BDNF in the
central nervous system was found associated with hippocampal
apoptosis and brain atrophy. These decreases were concomitant with
decreases in daily activity and weight loss [31]. An intriguing finding
emerged from a study using a murine model of MS (experimental
autoimmune encephalomyelitis [EAE]), in which exercise was found
to increase the level of BDNF in the central nervous system along with
an attenuation of disease severity [32]. It is then apparent that there
are ties between the expression of BDNF and exercise. In a human
population, decreased levels of BDNF were found at baseline in those
with MS as compared to controls. These levels were increased at week
four of an exercise intervention, but returned to baseline four weeks
later. An acute exercise intervention decreased BDNF levels in both
controls and patients with MS during a three hour post-exercise
period [33].
The finding of decreased BDNF in individuals with MS is not
unexpected [23,28], and may possibly be due to a lack of CD40
markers [23]. The decrease in peripheral BDNF may be reversible
through the administration of therapeutic agents in individuals with
MS [28,34-36]. The direct administration of cells over-expressing
BDNF into the central nervous system of EAE mice has been shown to
lead to a less severe form of EAE [37]. The increased levels of BDNF
may then have a neuroprotective effect [38] and prevent cellular
apoptosis [39]. In turn, BDNF may mediate the release of other
immune proteins in the periphery [40]. Murine work has
demonstrated the presence of CNS lesion can result in a decrease in
the expression of BDNF, leading to a decrease in reparative
mechanisms [41]. A similar finding has been demonstrated in human
subjects with MS, finding decreased BDNF secretion within the brain
to be associated with an increase in disease duration [42].
Other work has found a relative increase in BDNF concentrations
on the part of MS patients as compared with controls and those with
other neurologic disease states [43]. It is also possible that the
particular isoform of BDNF may vary, with MS patients displaying
lower levels of mature BDNF in serum [44].
Considering the increasing body of literature demonstrating
disruption of immunologic pathways in individuals with CFS [2,3,45],
it is important to investigate other potential disease correlates. In a
murine model of CFS, a polyphenolic activator (Resveratrol) has been
found to increase hippocampal size and improve daily running [46].
The findings from this study and the present provide evidence for
BDNF in the pathogenic process of CFS.
Limitations
As an initial pilot study, the CFS sample size was relatively small. It
will be beneficial for future studies to examine for the presence of
neurotrophins in a larger sample. Also, as this was a pilot study, the
focus was on BDNF and other neurotrophins were not evaluated.
Examining for the presence of other such proteins may provide
additional evidence in relation to the disease process.
Conclusion
The decreased production of BDNF on the part of MS patients is
consistent with the literature. However, the decreased production in
those with CFS was unexpected and a novel finding. This finding
could reflect a reduced ability to maintain neuronal structure and
function in those with CFS. Future studies are needed to evaluate for
neuronal damage in those with CFS.
Acknowledgement
The authors wish to thank George Siegel, MD; Chief, Neurology
Service, Edward Hines Jr. VA Hospital for his assistance in recruiting
and screening patients with multiple sclerosis.
References
1. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, et al.
(1999) A community-based study of chronic fatigue syndrome. Arch
Intern Med 159: 2129-2137.
2. Jason L, Sorenson M, Sebally K, Alkazemi D, Lerch A, et al. (2011)
Increased HDAC in association with decreased plasma cortisol in older
adults with chronic fatigue syndrome. Brain Behav Immun 25:
1544-1547.
3. Jason LA, Sorenson M, Porter N, Belkairous N (2011) An Etiological
Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Neurosci Med 2: 14-27.
4. Torres-Harding S, Sorenson M, Jason L, Maher K, Fletcher MA, et al.
(2008). The associations between basal salivary cortisol and illness
symptomatology in chronic fatigue syndrome. J Appl Biobehav Res, 13:
157-180.
5. Torres-Harding S, Sorenson M, Jason LA, Maher K, Fletcher MA (2008)
Evidence for T-helper 2 shift and association with illness parameters in
chronic fatigue syndrome (CFS). Bull IACFS ME 16: 19-33.
6. Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG (2001).
Cytokine and other immunologic markers in chronic fatigue syndrome
and their relation to neuropsychological factors. Applied
neuropsychology 8: 51-64.
7. Klimas NG, Salvato FR, Morgan R, Fletcher MA (1990) Immunologic
abnormalities in chronic fatigue syndrome. J Clin Microbiol 28:
1403-1410.
8. Fletcher MA, Maher KJ, Klimas NG (2002). Natural killer cell function in
chronic fatigue syndrome. Clinical and Applied Immunology Reviews, 2:
0020129-139.
9. Morris G, Maes, M (2013). Myalgic encephalomyelitis/chronic fatigue
syndrome and encephalomyelitis disseminata/multiple sclerosis show
remarkable levels of similarity in phenomenology and neuroimmune
characteristics. BMC Med 11: 205.
10. Boccaccio GL, Steinman L (1996) Multiple sclerosis: from a myelin point
of view. J Neurosci Res 45: 647-654.
11. Bakshi R (2003) Fatigue associated with multiple sclerosis: diagnosis,
impact and management. Mult Scler 9: 219-227.
12. Amato MP, Ponziani G, Rossi F, Liedl CL, Stefanile C, et al. (2001)
Quality of life in multiple sclerosis: the impact of depression, fatigue and
disability. Mult Scler 7: 340-344.
13. Bakshi R, Shaikh ZA, Miletich RS, Czarnecki D, Dmochowski J, et al.
(2000) Fatigue in multiple sclerosis and its relationship to depression and
neurologic disability. Mult Scler 6: 181-185.
14. Flachenecker P, Kümpfel T, Kallmann B, Gottschalk M, Grauer O, et al.
(2002) Fatigue in multiple sclerosis: a comparison of different rating
scales and correlation to clinical parameters. Mult Scler 8: 523-526.
15. Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, et al. (2004)
Cytokine mRNA expression in patients with multiple sclerosis and
fatigue. Mult Scler 10: 165-169.
16. Lange G, DeLuca J, Maldjian JA, Lee H, Tiersky LA, et al. (1999) Brain
MRI abnormalities exist in a subset of patients with chronic fatigue
syndrome. J Neurol Sci 171: 3-7.
17. Yan Q, Rosenfeld RD, Matheson CR, Hawkins N, Lopez OT, et al. (1997)
Expression of brain-derived neurotrophic factor protein in the adult rat
central nervous system. Neuroscience 78: 431-448.
18. Ziemssen T, Kümpfel T, Klinkert WE, Neuhaus O, Hohlfeld R (2002)
Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce
BDNF: implications for multiple sclerosis therapy. Brain-derived
neurotrophic factor. Brain 125: 2381-2391.
Citation: Sorenson M, Jason L, Peterson J, Herrington J, Mathews H (2014) Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue
Syndrome and Multiple Sclerosis. J Neurol Neurophysiol S12: S2-013. doi:10.4172/2155-9562.S12-013
Page 5 of 6
J Neurol Neurophysiol Neurodegenerative Diseases: Symptoms and
Therapeutics
ISSN:2155-9562 JNN, an open access journal

19. Dawood T, Anderson J, Barton D, Lambert E, Esler M, et al. (2007)
Reduced overflow of BDNF from the brain is linked with suicide risk in
depressive illness. Mol Psychiatry 12: 981-983.
20. Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular
theory of depression. Arch Gen Psychiatry 54: 597-606.
21. Kuipers SD, Bramham CR (2006) Brain-derived neurotrophic factor
mechanisms and function in adult synaptic plasticity: new insights and
implications for therapy. Curr Opin Drug Discov Devel 9: 580-586.
22. Chen L, Lawlor DA, Lewis SJ, Yuan W, Abdollahi MR, et al. (2008).
Genetic association study of BDNF in depression: Finding from two
cohort studies and a meta-analysis. Am. J. Med. Genet. Part B
Neuropsychiatr. Genet. American Journal of Medical Genetics, Part B:
Neuropsychiatric Genetics, 147: 814-821.
23. Azoulay D, Urshansky N, Karni A (2008) Low and dysregulated BDNF
secretion from immune cells of MS patients is related to reduced
neuroprotection. J Neuroimmunol 195: 186-193.
24. Rasmussen P, Brassard P, Adser H, Pedersen MV, Leick L, et al. (2009)
Evidence for a release of brain-derived neurotrophic factor from the
brain during exercise. Exp Physiol 94: 1062-1069.
25. Gold SM, Schulz KH, Hartmann S, Mladek M, Lang UE, et al. (2003).
Basal serum levels and reactivity of nerve growth factor and brain-
derived neurotrophic factor to standardized acute exercise in multiple
sclerosis and controls. J Neuroimmunol 138: 99-105.
26. Chen R, Moriya J, Yamakawa J, Takahashi T, Li Q, et al. (2008) Brain
atrophy in a murine model of chronic fatigue syndrome and beneficial
effect of Hochu-ekki-to (TJ-41). Neurochem Res 33: 1759-1767.
27. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, et al. (2005)
Diagnostic criteria for multiple sclerosis: 2005 revisions to the
"McDonald Criteria". Ann Neurol 58: 840-846.
28. Azoulay D, Vachapova V, Shihman B, Miler A, Karni A (2005) Lower
brain-derived neurotrophic factor in serum of relapsing remitting MS:
reversal by glatiramer acetate. J Neuroimmunol 167: 215-218.
29. Sepulcre J, Masdeu JC, Goñi J, Arrondo G, Vélez de Mendizábal N, et al.
(2009) Fatigue in multiple sclerosis is associated with the disruption of
frontal and parietal pathways. Mult Scler 15: 337-344.
30. Onen Sertoz O, Tolga Binbay I, Koylu E, Noyan A, Yildirim E, et al.
(2008) The role of BDNF and HPA axis in the neurobiology of burnout
syndrome. Prog Neuropsychopharmacol Biol Psychiatry 32: 1459-1465.
31. Bernardes D, Oliveira-Lima OC, Silva TV, Faraco CC, Leite HR, et al.
(2013) Differential brain and spinal cord cytokine and BDNF levels in
experimental autoimmune encephalomyelitis are modulated by prior and
regular exercise. J Neuroimmunol 264: 24-34.
32. Castellano V, White LJ (2008) Serum brain-derived neurotrophic factor
response to aerobic exercise in multiple sclerosis. J Neurol Sci 269: 85-91.
33. Blanco Y, Moral EA, Costa M, Gomez-Choco M, Torres-Peraza JF, et al.
(2006). Effect of glatiramer acetate (Copaxone) on the
immunophenotypic and cytokine profile and BDNF production in
multiple sclerosis: a longitudinal study. Neurosci Lett 406: 270-275.
34. Caggiula M, Batocchi AP, Frisullo G, Angelucci F, Patanella AK, et al.
(2006). Neurotrophic factors in relapsing remitting and secondary
progressive multiple sclerosis patients during interferon beta therapy.
Clin Immunol 118: 77-82.
35. Hamamcioglu K, Reder AT (2007) Interferon-beta regulates cytokines
and BDNF: greater effect in relapsing than in progressive multiple
sclerosis. Mult Scler 13: 459-470.
36. Linker RA, Lee DH, Demir S, Wiese S, Kruse N, et al. (2010). Functional
role of brain-derived neurotrophic factor in neuroprotective
autoimmunity: therapeutic implications in a model of multiple sclerosis.
Brain 133: 2248-2263.
37. Bayas A, Hummel V, Kallmann BA, Karch C, Toyka KV, et al. (2002)
Human cerebral endothelial cells are a potential source for bioactive
BDNF. Cytokine 19: 55-58.
38. De Santi L, Cantalupo L, Tassi M, Raspadori D, Cioni C, et al. (2009)
Higher expression of BDNF receptor gp145trkB is associated with lower
apoptosis intensity in T cell lines in multiple sclerosis. J Neurol Sci 277:
65-70.
39. Bayas A, Kruse N, Moriabadi NF, Weber F, Hummel V, et al. (2003).
Modulation of cytokine mRNA expression by brain-derived
neurotrophic factor and nerve growth factor in human immune cells.
Neurosci Lett 335: 155-158.
40. VonDran MW, Singh H, Honeywell JZ, Dreyfus CF (2011) Levels of
BDNF impact oligodendrocyte lineage cells following a cuprizone lesion.
J Neurosci 31: 14182-14190.
41. Weinstock-Guttman B, Zivadinov R, Tamaño-Blanco M, Abdelrahman
N, Badgett D, et al. (2007) Immune cell BDNF secretion is associated
with white matter volume in multiple sclerosis. J Neuroimmunol 188:
167-174.
42. Gielen A, Khademi M, Muhallab S, Olsson T, Piehl F (2003). Increased
brain-derived neurotrophic factor expression in white blood cells of
relapsing-remitting multiple sclerosis patients. Scand J Immunol 57:
493-497.
43. Tongiorgi E, Sartori A, Baj G, Bratina A, Di Cola F, et al. (2012) Altered
serum content of brain-derived neurotrophic factor isoforms in multiple
sclerosis. J Neurol Sci 320: 161-165.
44. Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, et al. (2014) Role
of adaptive and innate immune cells in chronic fatigue syndrome/
myalgic encephalomyelitis. Int Immunol 26: 233-242.
45. Moriya J, Chen R, Yamakawa J, Sasaki K, Ishigaki Y, et al. (2011).
Resveratrol improves hippocampal atrophy in chronic fatigue mice by
enhancing neurogenesis and inhibiting apoptosis of granular cells. Biol
Pharm Bull 34: 354-359.
This article was originally published in a special issue, entitled:
"Neurodegenerative Diseases: Symptoms and Therapeutics", Edited by Dr.
Jin J Luo, Temple University School of Medicine, USA
Citation: Sorenson M, Jason L, Peterson J, Herrington J, Mathews H (2014) Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue
Syndrome and Multiple Sclerosis. J Neurol Neurophysiol S12: S2-013. doi:10.4172/2155-9562.S12-013
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J Neurol Neurophysiol Neurodegenerative Diseases: Symptoms and
Therapeutics
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