The Relationship Between Chronic OA Pain and Cognition Deficits in OA Patients.
Conditions: Knee Osteoarthritis, Neuroinflammatory Response
Sponsor: Kaohsiung Veterans General Hospital.

 
 
 
 
Kaohsiung Veterans General Hospital 
Research Program 
Program Name： 
The relationship between chronic OA pain and cognition deficits in OA patients.  
 
Expected Program Starting Date ~ End date：08/07/2019 ~04/22/2021 
 
Principal Investigator：Chun-Hsien Wen 
Co-Investigator：Yuan-Yi, Chia  
Chen Chen-Hsiu 
Chan Julie Yu-Hwa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
CONTENT 
A 
THESIS ABSTRACT ........................................................................................................................... 3 
B 
BACKGROUND AND PURPOSE ........................................................................................................ 5 
C 
METHODS AND STUDY PROCEDURE ............................................................................................ 13 
D 
EXPECTED WORK ITEMS AND SPECIFIC RESULTS ......................................................................... 16 

 
  
A 
THESIS ABSTRACT 
Key Words： 
[KEY1] Chronic pain 
[KEY2] osteoarthritis 
[KEY3] cognition deficits 
[KEY4]  
[KEY5] 
[KEY6] 
Program Abstract: 
In the previous studies, which revealed that because neural systems involved in 
cognition and pain processing are closely linked, they may affect with each other. In 
addition to sensory symptoms, cognitive functioning is thought to be affected in 
chronic pain patients. Pain uses cognitive resources, alters neural plasticity and 
affects expression and activity of a variety of chemical and cellular neuromediators. 
There are several brain regions such as amygdala and hippocampus which are most 
commonly activated during pain processing. 
Osteoarthritis (OA) of the knee is one of the leading causes of disability among 
noninstitutionalized elderly adults 
One population-based study revealed that osteoarthritis increases the risk of 
cognitive deficits diseases such as dementia. However the possible mechanism had 
not be elucidated. Recent study revealed that OA-induced hyperalgesia was 
associated with increased NGF/TrkA signaling. NGF activation of ERK/MAPK may play 
a role in centralization of OA pain. Otherwise NGF has also been shown to produce a 
dramatic 
upregulation 
of 
brain-derived 
neurotrophic 
factor 
(BDNF) 
in 
trkA-expressing DRG cells, and there is now growing evidence that BDNF may serve 
as a central regulator of excitability and is a neuromodulate or of central pain 
processing. On the other hand, in previous studies they showed that BDNF plays a 
critical role in synaptic plasticity, memory processes and storage of long-term 
memory. The BDNF/TrkB system in the hippocampus plays a crucial role not only in 
the memory acquisition, but also in the retention and / or recall of spatial memory. 
Besides ongoing pain in chronic knee OA is characterized by increased brain 
activity in limbic-affective regions thus providing novel evidence for a strong 
emotional component of arthritis pain. There are feedback loops exist between pain, 
emotion and cognition. How is the role of BDNF in such loop? Especially in circuit 
between amygdala and hippocampus? The objective of the study was the evaluation 
of association between pain characteristics and cognitive functions in severe knee 
OA patients. Besides, we will try to explore the possible mechanisms by which 
chronic OA like pain develops to cognitive deficits in animal models. The relationship 
between BDNF levels in body fluids (serum and CSF) and pain characteristics and 

 
  
cognitive function was also evaluated in the whole sample. 
 

 
  
B 
BACKGROUND AND PURPOSE 
Importance and research status of this project at home and abroad, and indicate 
important documents。 
    The International Association for the Study of Pain (IASP) defines pain as ‘‘an 
unpleasant sensory or emotional experience associated with actual or potential tissue 
damage, or described in terms of such damage.’’ This definition is based on the 
concept of pain as a perception rather than as a purely sensory modality, and consider 
the fact that for pain to be consciously experienced, cognitive processing is required. 
Thus in 2016, Williams, A.C. et al [1] proposed an updated definition of pain as ‘’Pain is 
a distressing experience associated with actual or potential tissue damage, with 
sensory, emotional, cognitive and social components.’’ The authors added cognitive 
and social components in pain definition. They may have hypothesized that because 
neural systems involved in cognition and pain processing are closely linked, they may 
affect with each other. 
  Chronic pain is defined as pain persisting for 3–6 months or longer generally 
exceeds the duration of the precipitating noxious stimulus or injury, and may be 
neuropathic, inflammatory or idiopathic in nature [2]. Chronic pain are most common 
reasons for seeking medical attention and is reported by 20 to 50 percent of patients 
seen in primary care [3]. In addition to sensory symptoms, cognitive functioning is 
thought to be affected in chronic pain patients. 
  There was a detailed review in 2011 [4], Moriarty, O. et al. reviewed both clinical 
and preclinical studies that have investigated pain-related alterations in cognition. In 
some previous studies they reviewed, which showed that chronic pain patients 
performing poorly compared with controls on some cognitive function such as spatial, 
verbal, working memory capacity and recall, recognition memory, long-term spatial 
memory and general cognition. In chronic pain of animal models, both inflammatory 
pain and neuropathic pain models revealed decreased cognitive performance in 
chronic pain animals. In this review the authors have proposed a model to explain the 

 
  
potential mechanisms involved in pain-related cognitive impairment. This model is 
based on the three theories of (1) competing limited resources, (2) neuroplasticity and 
(3) dysregulated neurochemistry. Pain uses cognitive resources, alters neural plasticity 
and affects expression and activity of a variety of chemical and cellular 
neuromediators. There are six brain regions most commonly activated during pain 
processing: the insular cortex, the prefrontal cortex, the anterior cingulate cortex, 
periaqueductal gray, amygdala and hippocampus. 
  Considering feasibility of biological fluids collection in clinical settings, I would like to 
more explore neuromediator theory for further study. Besides considering patient in 
my clinical settings, I would like to choose osteoarthritic (OA) like pain model for 
further study.  
  In a study of Annals of Rheumatic diseases in 2016 [5], it revealed that OA-induced 
hyperalgesia was independent of joint pathology and were strong correlated with 
augmentation of nerve growth factor(NGF)/ tropomyosin receptor kinase A (TrkA) 
signaling. This study revealed that whether in mice synovium or in OA patient’s 
synovium, OA-induced hyperalgesia was associated with increased NGF/TrkA signaling. 
Thus, the authors proposed that NGF activation of ERK/MAPK may play a role in 
centralization of OA pain. Initially, NGF/TrkA signaling promotes peripheral 
sensitization in the OA joint, then retrograde transport to dorsal root ganglion (DRG), 
amplification of input resulted in central sensitization. 
  NGF has also been shown to produce a dramatic upregulation of brain-derived 
neurotrophic factor (BDNF) in trkA-expressing DRG cells, and there is now growing 
evidence that BDNF may serve as a central regulator of excitability [6].  
  Among neurotrophins, BDNF is the most abundant and widely distributed in the 
central nervous system. BDNF is expressed in small and medium-sized sensory neurons 
of the DRG, and is synthesized by the type of DRG cells which express trkA and 
neuropeptide CGRP [7]. The expression of BDNF mRNA and protein is dramatically 
up-regulated in models of inflammatory pain. 

 
  
  In the previous study [8], they administrated systemic NGF treatment, a procedure 
that mimics peripheral inflammatory states, it resulted in raises BDNF levels in sensory 
neurons and increases nociceptive spinal reflex excitability. This increased central 
excitability is reduced by trkB-IgG, a BDNF “antagonist.” And if with intrathecally 
administered NGF, it has much more potent effects than systemic NGF on BDNF levels 
[7]. Thus, we know that BDNF is a neuromodulator of central pain processing. 
  How is the exact role of BDNF in central sensitization pain from peripheral 
nociceptors, to spinal level and brain level? In Rheumatology International 2014 [9], 
this study was to analyze the levels of BDNF in both the plasma and synovial fluid of 
patients with primary knee osteoarthritis compared with control individuals and to 
investigate the relationship between BDNF levels and self-reported pain. This study 
showed systemic BDNF (i.e., plasma levels) of the knee OA patients were significantly 
higher than that of the healthy controls, but synovial fluid BDNF levels are normal. And 
plasma BDNF levels significantly correlated with self-reported pain (Western Ontario 
and mcmaster universities Osteoarthritis Index, WOMAC). In spinal level, previous 
animal studies have shown that inflammation is accompanied by an upregulation of 
BDNF in both types of ganglia. Microglia have been identified as a major source for the 
synthesis and release of BDNF responsible for increasing neuronal excitability by 
causing disinhibition in dorsal horn neurons in the spinal cord [10]. In DMM OA animal 
model, which leads to late stage dorsal horn microgliosis. The microgliosis is associated 
with joint damage and accompanying persistent pain [11]. At the brain level, BDNF has 
also been shown to activate descending nociceptive facilitation in the nucleus raphe 
magnus, periaqueductal gray, and rostral ventromedial medulla. In which brain 
regions, BDNF shifts the balance from descending nociceptive inhibition toward 
nociceptive facilitation [12-14]. Previous study reported that under chronic stress, it 
leads to increased BDNF mRNA and protein level in basal lateral amygdala [15]. 
However, BDNF level is decreased in the hippocampus, include subfields CA1, CA2, and 
CA3 either in acute pain or chronic pain and stress (acute or chronic treatments) [16, 

 
  
17]. 
  On the other hand, in previous studies they showed that BDNF plays a critical role in 
synaptic plasticity, memory processes and storage of long-term memory [18, 19]. In 
one animal models study [18], BDNF is released in the hippocampus of well-taught rats 
during maze performance, and thereby TrkB activation is seen immediately after the 
maze training. The BDNF/TrkB system in the hippocampus plays a crucial role not only 
in the memory acquisition, but also in the retention and / or recall of spatial memory. 
  According the above studies, we know that BDNF level are increased both in 
peripheral nociceptors and at the spinal level. In brain level, BDNF level increased in 
nucleus raphe magnus, periaqueductal gray, rostral ventromedial medulla, amygdala. 
Except in hippocampus, BDNF level is decreased. Why is discrepancy of BDNF level in 
brain regions? Especially between amygdala and hippocampus, they are important 
regions of modulating pain and memory function. The amygdala is specialized for input 
and processing of emotion, while the hippocampus is essential for declarative or 
episodic memory [20]. Is there any specific pathway between these two regions? 
There are some recent studies to illustrate how amygdala and hippocampus work 
synergistically to form long-term memory. The basolateral amygdala nucleus (BL) is 
divided into anterior part (BLa) and posterior part (BLp). Both BLa and BLp project 
directly to ventral hippocampal CA1 (vCA1). BLp–vCA1 projection is more intensive 
than BLa–vCA1 projection [20]. Activation of BLa–vCA1 inputs induces anxiety and 
social deficits [21]. Activation of BLp–vCA1 inputs control emotion-modulated spatial 
memory [22]. From the above animal studies, we noted that circuits between BLA and 
hippocampus CA1 regions control emotional and cognitive expression. So, how is the 
affective effect in OA patients? From the PET image findings, in which revealed 
arthritic pain is associated with increased activity in areas of the brain that play a role 
in affect, aversive conditioning, and motivational responses [23]. Besides by use of 
arterial spin labelling (ASL) MRI for cerebral blood flow mapping, which showed that 
areas with significant associations between CBF and reported ongoing OA pain 

 
  
intensity additionally controlled for pain catastrophizing and trait-anxiety scores [24]. 
Ongoing pain in chronic knee OA is characterized by increased brain activity in 
limbic-affective regions thus providing novel evidence for a strong emotional 
component of arthritis pain [24]. According the above studies, which revealed that 
pain can have a negative effect on emotions. Conversely, a negative emotional state 
can lead to increased pain, whereas a positive state can reduce pain and improve 
cognition. There are feedback loops exist between pain, emotion and cognition [25]. 
How is the role of BDNF in such loop? Especially in circuit between amygdala and 
hippocampus? 
  As for clinical study, there is a study[26] used Taiwan National Health Insurance 
Research Database (NHIRD) data base which revealed that osteoarthritis increases the 
risk of dementia. The adjusted hazard ratio(HR) for dementia was 1.25 for patients 
with OA. The results of this study indicated that OA is an independent risk factor for 
dementia. The authors proposed that inflammation and depressed symptoms are 
possible mechanisms of OA which develop dementia.  
Therefore, the objective of the study was the evaluation of association between pain 
characteristics and cognitive functions in severe knee OA patients. The relationship 
between BDNF levels in body fluids (serum and CSF) and pain characteristics and 
cognitive function was also evaluated in the whole sample. 
 
References：  
1. 
Williams, A.C. and K.D. Craig, Updating the definition of pain. Pain, 2016. 
157(11): p. 2420-2423. 
2. 
Aguggia, M., Neurophysiology of pain. Neurol Sci, 2003. 24 Suppl 2: p. S57-60. 
3. 
Elliott, A.M., et al., The epidemiology of chronic pain in the community. Lancet, 
1999. 354(9186): p. 1248-52. 
4. 
Moriarty, O., B.E. McGuire, and D.P. Finn, The effect of pain on cognitive 
function: a review of clinical and preclinical research. Prog Neurobiol, 2011. 

 
  
93(3): p. 385-404. 
5. 
Kc, R., et al., PKCdelta null mutations in a mouse model of osteoarthritis alter 
osteoarthritic pain independently of joint pathology by augmenting 
NGF/TrkA-induced axonal outgrowth. Ann Rheum Dis, 2016. 75(12): p. 
2133-2141. 
6. 
Pezet, S., M. Malcangio, and S.B. McMahon, BDNF: a neuromodulator in 
nociceptive pathways? Brain Res Brain Res Rev, 2002. 40(1-3): p. 240-9. 
7. 
Michael, G.J., et al., Nerve growth factor treatment increases brain-derived 
neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and 
in their central terminations within the spinal cord. J Neurosci, 1997. 17(21): p. 
8476-90. 
8. 
Kerr, B.J., et al., Brain-derived neurotrophic factor modulates nociceptive 
sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci, 
1999. 19(12): p. 5138-48. 
9. 
Simao, A.P., et al., Involvement of BDNF in knee osteoarthritis: the relationship 
with inflammation and clinical parameters. Rheumatol Int, 2014. 34(8): p. 
1153-7. 
10. 
Ferrini, F. and Y. De Koninck, Microglia control neuronal network excitability via 
BDNF signalling. Neural Plast, 2013. 2013: p. 429815. 
11. 
Tran, P.B., et al., Spinal microglial activation in a murine surgical model of knee 
osteoarthritis. Osteoarthritis Cartilage, 2017. 25(5): p. 718-726. 
12. 
Tao, W., et al., Persistent inflammation-induced up-regulation of brain-derived 
neurotrophic 
factor 
(BDNF) 
promotes 
synaptic 
delivery 
of 
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 
acid 
receptor 
GluA1 
subunits in descending pain modulatory circuits. J Biol Chem, 2014. 289(32): p. 
22196-204. 
13. 
Zhang, Z., et al., Brain-derived neurotrophic factor-mediated downregulation of 
brainstem K+-Cl- cotransporter and cell-type-specific GABA impairment for 

 
  
activation of descending pain facilitation. Mol Pharmacol, 2013. 84(4): p. 511-20. 
14. 
Guo, W., et al., Supraspinal brain-derived neurotrophic factor signaling: a novel 
mechanism for descending pain facilitation. J Neurosci, 2006. 26(1): p. 126-37. 
15. 
Bennett, M.R. and J. Lagopoulos, Stress and trauma: BDNF control of 
dendritic-spine formation and regression. Prog Neurobiol, 2014. 112: p. 80-99. 
16. 
Duric, V. and K.E. McCarson, Neurokinin-1 (NK-1) receptor and brain-derived 
neurotrophic factor (BDNF) gene expression is differentially modulated in the rat 
spinal dorsal horn and hippocampus during inflammatory pain. Mol Pain, 2007. 
3: p. 32. 
17. 
Duric, V. and K.E. McCarson, Persistent pain produces stress-like alterations in 
hippocampal neurogenesis and gene expression. J Pain, 2006. 7(8): p. 544-55. 
18. 
Yamada, K. and T. Nabeshima, Brain-derived neurotrophic factor/TrkB signaling 
in memory processes. J Pharmacol Sci, 2003. 91(4): p. 267-70. 
19. 
Bekinschtein, P., et al., BDNF and memory formation and storage. Neuroscientist, 
2008. 14(2): p. 147-56. 
20. 
Yang, Y. and J.Z. Wang, From Structure to Behavior in Basolateral 
Amygdala-Hippocampus Circuits. Front Neural Circuits, 2017. 11: p. 86. 
21. 
Felix-Ortiz, A.C., et al., BLA to vHPC inputs modulate anxiety-related behaviors. 
Neuron, 2013. 79(4): p. 658-64. 
22. 
Yang, Y., et al., Opposite monosynaptic scaling of BLP-vCA1 inputs governs 
hopefulness- and helplessness-modulated spatial learning and memory. Nat 
Commun, 2016. 7: p. 11935. 
23. 
Kulkarni, B., et al., Arthritic pain is processed in brain areas concerned with 
emotions and fear. Arthritis Rheum, 2007. 56(4): p. 1345-54. 
24. 
Cottam, W.J., et al., Associations of limbic-affective brain activity and severity of 
ongoing chronic arthritis pain are explained by trait anxiety. Neuroimage Clin, 
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Bushnell, M.C., M. Ceko, and L.A. Low, Cognitive and emotional control of pain 

 
  
and its disruption in chronic pain. Nat Rev Neurosci, 2013. 14(7): p. 502-11. 
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表單G4 

 
  
C 
METHODS AND STUDY PROCEDURE 
 
This study was approved from the Institutional Review Board of Kaohsiung veterans 
general hospital (IRB No. VGHKS19-CT2-21). Written informed consent was received 
from the OA and control group patients before their participation in the study. We 
totally enrolled 60 patients (30 OA group and 30 control group) who were scheduled 
to receive elective surgery which need spinal anesthesia.  
l The inclusion criteria of OA group are:  
1. Age is more than 20 years old,  
2. American Society of Anesthesiologists (ASA) class I–III.  
l The exclusion criteria of OA group are:  
1. Unwilling to participate,  
2. age is lesser than 20 years old,  
3. autoimmune diseases,  
4. previous knee injury or infection history,  
5. brain region disease ex: stroke or brain tumor...etc,  
6. mild cognitive impairment, dementia or other neurogenerative diseases,  
7. cancer, and  
8. other chronic pain. 
Control group patients were included based on ASA class I–III, age > 20 years old, 
scheduled to receive elective general surgery or urological surgery with spinal 
anesthesia such as hernioplasty, ureteroscopy and laser stone fragmentation, and 
transurethral resection of the prostate…etc. The exclusion criteria of control group are 
the same as those of OA group patients plus with OA pain.  
All patients will receive the following questionnaires on the day before their surgery: 
the Western Ontario and McMaster universities Osteoarthritis Index (WOMAC) and 
the cognitive abilities screening instrument (CASI). Otherwise, we used geriatric 
depression scale (GDS-15) for evaluation of emotion especially for participant of age > 
65 years old.  
 

 
 
 
VGHKS19-CT2-21   CASE REPORT 
Case Report Form                                       Case No:                
I Basic information：       
No.：          Sex：£1.M £2.F 
Age：    Weight：  kg Height：  cm BMI：    kg/m2 
Date：  /  /       ASA：   
Group：□1. Osteoarthritis group  □2. Control group 
II History： 
□Smoking   □Drinking   □Education level(□Junior high school, □Senior high school,  
□University, □Graduate school) 
  □HTN □DM □Autoimmune disease □Hyperlipidemia □CAD □COPD 
□CVA   □Parkinson disease  □Painkillers(□No □Yes，        ) 
□Duration of pain(□<=Three months □3~6 months □> 6 months 
III Results of questionnaires 
1. CASI C-2.0 
LTM 
STM 
ATTEN 
MENMA 
ORIEN 
ABSTR 
LANG 
DRAW 
ANML 
CASI MMSE 
 
 
 
 
 
 
 
 
 
 
 
2. WOMAC  
Pain 
Stiffness 
Body function 
Total score:  / 96 =   % 
 
 
 
 
3. GDS-15 
Total score 
1(0-4) 
2(5-9) 
3(10-15) 
 
 
 
 
IV Postoperative evaluation  
1. □Headache：□0 None □1 Mild □2 Moderate □3 Severe 
2. □Lumbar soreness/Backache：□0 None □1 Mild □2 Moderate □3 Severe 
3. □Nausea/Vomiting：□0 None □1 Mild □2 Moderate □3 Severe 
4. □Side effects of blood extraction：□Bruises □Infection 

 
 
 

 
 
 
D 
EXPECTED WORK ITEMS AND SPECIFIC RESULTS 
 
Contribution to clinical or academic 
Through this study, it is expected to explore the associations of cognitive 
deficits caused by knee osteoarthritis.