臺灣博碩士論文加值系統

背景/目的： 巴金森氏症(Parkison's disease)的診斷和治療目前仍被視為是一大挑戰。本研究的目的是要探討針刺留針(Retained acupuncture)對神經毒素誘發的巴金森氏症小鼠模型在治療上的角色，以及分析用非侵入性方法測量巴金森氏症病患手部顫抖與臨床表現的相關性。

方法： 在動物實驗方面，採用雄性C57BL/6小鼠注射1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) 誘發出巴金森氏症模型的方法。首先，將健康雄性C57BL/6小鼠雄性分成四組進行實驗：第一組-正常組(注射生理食鹽水代替神經毒素)，第二組-注射MPTP+留針組(RA)，第三組-注射MPTP+電針組(Electro acupuncture , EA)，第四組-注射MPTP+偽針組(Sham acupuncture,SA)。除了正常組，每一組依組別先進行兩次各別不同方式的針刺大陵(PC7)穴刺激後，連續注射15mg/kg/d 的MPTP五天，再進行一次針刺刺激，然後將各組小鼠進行爬桿(pole test)的行為改變測試試驗。隨後將小鼠犧牲，取出大腦組織進行高效能液相層析法(High Performance Liquid Chromatography, HPLC)分析神經元細胞的多巴胺(dopamine)和代謝產物濃度，以及分別用免疫組織化學染色 (immunohistochemistry staining) 方法與西方墨點(Western blotting)法分析含tyrosine hydroxylase (TH) 細胞數目和其濃度。再以碘123-(S)-(一)-3-碘-2-羥基-6-甲氧基-N- [(1-乙基-2-吡咯烷基)]苯酰胺 (iodobenzamide, IBZM)(全名: [ 123I] IBZM (l23I-S-(-)-N-[(l-ethyl-2-pyirolidinyl) methyl] -2-hydroxy-3-iodo-6-rnethoxybenzarnide)為放射源的單光子放射電腦斷層掃描([123I] IBZM-Single-photon Emission Computed Tomography (SPECT) imaging)比較針刺留針組(RA)與偽針組(SA)的腦部影像差異。
在臨床研究部分，試驗過程中分別以四種不同模式姿勢來偵測巴金森氏症病患手部振顫的頻率。包括：
模式一：在單側手靜態平放姿勢下測量單手的振動頻率。
模式二：在雙側手靜態平放姿勢下測量其中一隻單手的振動頻率。
模式三：在單側手靜態平舉姿勢下測量單手的振動頻率。
模式四：在雙側手靜態平舉姿勢下測量其中一隻單手的振動頻率。
單手的振動頻率測量是採用雷射光線三角測量(laser line triangulation measurement (LLTM))方法，以雷射光線照射受測手部位，再擷錄此部位影像，將影像檔輸入電腦後，以測量分析軟體進行分析。

結果： 動物實驗結果顯示：接受過針刺刺激與MPTP注射的三個組小鼠，在行為改變測試中，爬桿(從頂端至底部)時間明顯比正常組 (4.33 ± 0.15 sec) 長。然而，第二組(留針組，RA) (7.13 ±0.20 sec)爬桿時間比第四組(偽針組，SA) (7.89 ± 0.46 sec)短。免疫組織化學染色法實驗中，含酪氨酸羥化酶（Tyrosine hydroxylase, TH)的神經元細胞(TH+)數目，和西方墨點法測得酪氨酸羥化酶濃度，第二組(留針組，RA)都比第三組(電針組，EA)和第四組(偽針組，SA) 高。在單光子放射電腦斷層掃描([123I] IBZM-SPECT imaging)中，第二組(留針組，RA)也被發現碘123在腦部紋狀體的吸收比第四組(偽針組，SA) 高。
在對巴金森氏症病患手部振顫的測量結果，發現發病年齡和模式一(單手平放)的左手、非慣用手與模式二(雙手平放)的非慣用手的振顫頻率具明顯相關性。此外，病程時間長度與模式一(單手平放)的左手、非慣用手與模式三(單手平舉)的左手及模式四(雙手平舉)的右手、慣用手振顫頻率皆具明顯正相關性。

結論： 我們發現針刺留針(RA)刺激，可以減輕MPTP誘發的巴金森氏症小鼠腦部神經元細胞損傷，顯示其在治療人類的巴金森氏症當中，可能是有用的輔助治療方法。此外，雷射光線三角測量法(LLTM)也顯示是一種有效、非侵入性的測量手部振顫方法，可以運用在巴金森氏症病患的早期診斷上。

Background/aim: The diagnosis and treatment of Parkison’s disease remains a challenging problem. The aim of this study was to investigate the role of retained acupuncture (RA) in neurotoxin-induced Parkinson’s disease (PD) mice and to correlate hand tremors analyzed by a non-invasive method with clinical manifestation among PD patients.

Method: In animal study, male C57BL/6 mice were injected with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) to induce the PD model. The mice were divided into four groups, namely, ( 1) normal; (2) MPTP + retained acupuncture (RA);( 3) MPTP + electroacupuncture (EA); (4) MPTP + sham acupuncture (SA). After mice being manipulated twice with/without acupuncture at acupoints (Daling, PC 7), groups 2-4 were injected with MPTP (15 mg/kg/d). The mice were evaluated for behavioral changes, in terms of time of landing, after another acupuncture treatment. The animals were sacrificed and their brains assayed for dopamine and its metabolites and tyrosine hydroxylase (TH) expression by using HPLC and immunohistochemistry /Western blotting, respectively. [123I] IBZM-SPECT imaging between SA and RA groups were compared.
In human study, there were four modes in tremor detection during each testing session in PD patients, namely, Mode 1, single hand tremor detected during a single resting hand posture; Mode 2, single hand tremor detected during paired resting hands posture; Mode 3, single postural hand tremor detected during a single (lifting) hand posture; and Mode 4, single postural hand tremor detected during paired (lifting) hands posture. The hand tremor was detected using a laser line triangulation measurement method and the image was stored on a video system after acquisition from a computer and analyzed off-line.

Results: The results of animal study showed that the time of landing of the three groups with treatment was significant longer than group 1(normal) (4.33 ± 0.15 sec). Nonetheless, group 2 (RA) (7.13 ±0.20 sec) had a shorter time of landing than group 4 (SA) (7.89 ± 0.46 sec). The number of TH (+) neurons and the expression of TH proteins were significantly higher in the RA group than in the SA/ EA groups. RA also increased the uptake of [123I] IBZM into the striatum compared to the SA group.
The results of hand tremor detection showed a significant correlation between age at disease onset and tremor frequency obtained from the left hand, tremor frequency obtained from the non-dominant hand using Mode 1(single, resting) and tremor frequency obtained from the non-dominant hand using Mode 2(both, resting). Furthermore, there was a significant positive correlation between disease duration and tremor frequency obtained from the left hand, tremor frequency obtained from the non-dominant hand using Mode 1(single, resting), tremor frequency obtained from lifting the left hand using Mode 3(single, postural), tremor frequency obtained from lifting the right hand and tremor frequency obtained from lifting the dominant hand in Mode 4(both, postural).

Conclusion: We conclude that RA possibly attenuates neuronal damage in MPTP-induced PD mice, which suggests RA may be useful as a complementary strategy when treating human PD. Moreover, the laser line triangulation measurement is a non-invasive method that can detect tremor early in the course of patients diagnosed with PD.

Table of Contents
1. Introduction...........................................1
1.1 Complementary and alternative medicine and Traditional Chinese medicine..............................1
1.2 Parkinson's disease (PD)..........................5
1.3 Clinical manifestations of Parkinson's disease.....5
1.4 Pathogenesis and etiology of Parkinson's disease...6
1.5 Parkinson's disease interpreted in traditional medicine..................................................6
1.6 Diagnosis of Parkinson's disease...................7
1.7 Treatment of Parkinson's disease..................10
1.8 Rationale and aim of the study....................12

2. Subjects, Material and Method.........................13
2.1 Animal model--Acupuncture effect in neurotoxin-induced PD mice..........................................13
2.1.1 Animal.........................................13
2.1.2 PD model and Study groups......................13
2.1.3 Behavioral test Detection by LLTM method in MPTP-induced mice.............................................15
2.1.4 Immunohistochemistry for tyrosine hydroxylase (+) neuron.................................................. 15
2.1.5 Western blot analysis for tyrosine hydroxylase.16
2.1.6 Analysis of dopamine (DA) and its metabolite levels, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in MPTP-induced PD mice as measured by HPLC.........................................17
2.1.7 Acquisition of single photon emission computed tomography (SPECT) images of the MPTP-induced PD mice....17
2.1.8 Statistics.....................................18
2.2 Clinical study--Hand tremor detection and acupuncture effect in patients with PD...................19
2.2.1 Subject recruitment............................19
2.2.2 Device and experimental setup..................20
2.2.3 Detection of hand tremors by novel laser line triangulation measurement method.........................20
2.2.4 Image acquisition and data analysis............22
2.2.5 Statistics.....................................22

3. Result
3.1 Neuroprotection effects of retained acupuncture in neurotoxin-induced PD....................................23
3.1.1 The MPTP induced neurological deficit and the decreased striatal dopamine level occur in a dose-dependent manner...................................................23
3.1.2 Effects of electroacupuncture (EA) and retained acupuncture (RA) on the behavior changes in the MPTP-induced PD mice..........................................23
3.1.3 Effects of electroacupuncture (EA) and retained acupuncture (RA) on TH expression as assessed by immunohistochemistry in MPTP-induced PD mice.............23
3.1.4 Effects of electroacupuncture (EA) and retained acupuncture (RA) on TH expression by Western blotting in MPTP-induced PD mice.....................................24
3.1.5 Effects of electroacupuncture (EA) and retained acupuncture (RA) on dopamine (DA) and its metabolites levels (DOPAC and HVA) in MPTP-induced PD mice as measured by HPLC..................................................24
3.1.6 SPECT imaging verified the effects of retained acupuncture (RA) on the SN of the MPTP-induced mice......24
3.1.7 Effect of a 5-HT2 receptor blocker on the MPTP-induced PD mice treated with acupuncture.................25
3.2 Hand tremor detection and acupuncture effect in patients with PD.........................................26
3.2.1 Correlation between frequency of hand tremor and age at PD onset..........................................26
3.2.2 Correlation between frequency of hand tremor and disease duration.........................................26
3.2.3 The hand dominance and the correlation between frequency of hand tremor and PD symptoms.................27
4. Discussion............................................28
4.1 Neuroprotection effects of retained acupuncture in neurotoxin-induced PD....................................28
4.1.1 6-OHDA and MPTP–induced animal model..........28
4.1.2 Principles of setup for EA, RA and SA..........29
4.1.3 Acupoints selection for PD treatment...........29
4.1.4 Proposed mechanism of acupuncture effect for PD treatment................................................30

4.2 Hand tremor detection and acupuncture effect in patients with PD.........................................34
4.2.1 Correlations between frequency of hand tremor and age at PD onset..........................................35
4.2.2 Correlation between frequency of hand tremor and PD duration..............................................36
4.2.3 The hand dominance and the correlation between frequency of hand tremor and PD symptoms.................37
4.2.4 Tremor detection in the animal model...........39

5. Conclusion............................................40
Reference................................................41
Appendix --Approved clinical trial consents by the Institutional Review Board of Taipei Veterans General Hospital.................................................79

 
LIST OF FIGURES..........................................56
FIG. 1 Protocols for acupuncture manipulation of the MPTP-induced PD mice..........................................56

FIG. 2 Schematic presentation of acupuncture manipulation.............................................57

FIG. 3 Schematic drawing of the system for LLTM method consisted of a laser diode, a laser driver, and a CMOS image sensor.............................................58

FIG. 4 Schematic drawing of 4 modes for hand tremor among Parkinson patients by the LLTM method according to the tested hand and hand status..............................59

FIG. 5 Validation of the neurotoxin-induced PD model. The parameters used to evaluate the effect of MPTP include a functional study for neurological deficit, in terms of time of landing by pole test (A), the presence of tyrosine hydroxylase (TH) (+) neurons by immunohistochemistry, both qualitatively (B) and quantitatively (C) substantia nigra pars compacta (SNpc).....................................60

FIG. 6 Effects of acupuncture on MPTP-induced PD mice. The parameters used to evaluate the effect of MPTP include a functional study for neurological deficit, in terms of time of landing by pole test (A), the presence of tyrosine hydroxylase (TH) (+) neurons by immunohistochemistry (B,C) and the expression of TH, which was quantified by Western blotting (D, E)..........................................63

FIG. 7 SPECT images of the acupuncture-treated MPTP-induced PD mice. SPECT images (A) were acquired of the SN areas from retained acupuncture (RA) and sham acupuncture (SA)-treated PD mice. The kinetics of [123I]IBZM uptake shown as relative normalized uptake count (B) was compared between MPTP+SA and MPTP+RA group........................66

FIG. 8 Effect of 5-HT2 receptor blocker on MPTP-induced PD mice treated with acupuncture. The parameters used to evaluate the effect of SB206553 on acupuncture treatment in MPTP-induced PD mice include a functional study for neurological deficit, in terms of time of landing by pole test (A), and, the presence of tyrosine hydroxylase (TH) (+) neurons by immunohistochemistry (B)..................67

FIG. 9 The tremor frequencies of the left hand (A) and the non-dominant hand using Mode 1 (B) show a negative correlation with age at onset among patients with PD.....69

FIG. 10 There is a positive correlation between PD duration and the frequencies of tremor for the left hand (A) and the non-dominant hand using Mode 1 (B) and the left hand using Mode 3 (C)....................................70

FIG. 11 A preliminary study was done to detect the tremor with LLLT in the animal model. Four groups including group A, an empty box, group B, empty box within a solid ball which weights 20g, group C, a C57BL/6 mice with normal saline injection and group D, a C57BL/6 mice with 3/4 dose MPTP injection, were detected with LLLT and their data were analyzed with the same method for human subjects described previously...............................................72
 
LIST OF TABLES...........................................73
TABLE 1. Detection modes for hand tremor among PD patients by the LLTM method according to the tested hand and hand status...................................................73

TABLE 2. Neurotransmitter concentrations in MPTP-induced PD mice treated with acupuncture............................74

TABLE 3. Demographic characteristics of the recruited Parkinson’s disease patients............................75

TABLE 4. Correlation of the frequency of hand tremor among patients with PD as assessed by the LLTM method and age at disease onset............................................76

TABLE 5. Correlation between frequency of the hand tremor among patients with PD as assessed by the LLTM method and disease duration.........................................77

SUPPLEMENTARY MATERIAL...................................78
TABLE 6. SPECT images verifying the effects of acupuncture on PD patients

ACRONYM TABLE
6-OHDA 6-hydroxydopamine
ANOVA analysis of variance
CAM complementary and alternative medicine
CAPIT core assessment program for intracerebral transplantation
CMOS complementary metal-oxide semiconductor
CNS central nervous system
COMT catechol-O-methyltransferase
CT computed tomography
DA dopamine
DOPAC 3,4-Dihydroxyphenylacetic acid
EA electroacupuncture
FFT fast fourier transformation
fMRI functional magnetic resonance imaging
HPLC high-performance liquid chromatography
HVA homovanillic acid
LLTM laser line triangulation measurement
MA manual acupuncture
MPTP 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine
NE norepinephrine
OSEM ordered subset expectation maximization
PD Parkinson's disease
PET positron emission tomography
RA retained acupuncture
RT room temperature
SA sham acupuncture
SN substantia nigra
SNpc substantia nigra pars compacta
SOMF second order moment function
SPECT single photon emission computed tomography
SUR specific uptake ratio
TCM traditional Chinese medicine
TENS transcutaneous electric nerve stimulation
TH tyrosine hydroxylase
UPDRS unified Parkinson's disease rating scale
VOI Volume-Of-Interest
WHO World Health Organization

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