Contributors |
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Preface: The evolving scenario of Parkinson's research |
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xix | |
Part I Basic science |
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Chapter 1 What we can learn from iPSC-derived cellular models of Parkinson's disease |
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1 | (26) |
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4 | (1) |
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2 Establishment of iPSC technology and methods of differentiation into DAns |
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5 | (2) |
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2.1 Establishment of induced pluripotent stem cells |
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5 | (1) |
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2.2 Differentiation into DAns |
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6 | (1) |
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3 iPSC-derived neurons for disease modeling |
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7 | (7) |
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3.1 Endoplasmic reticulum stress |
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10 | (1) |
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3.2 Protein trafficking and degradation deficits |
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11 | (1) |
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3.3 Mitochondrial defects and oxidative stress |
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12 | (2) |
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3.4 Alterations in calcium homeostasis |
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14 | (1) |
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4 iPSC-derived glial cells for disease modeling |
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14 | (1) |
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5 Co-culture systems, 3D cultures and organoids for disease modeling |
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15 | (2) |
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6 iPSC-derived neurons for cell-based treatments |
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17 | (1) |
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7 Limitations of iPSC-based models |
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17 | (1) |
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18 | (1) |
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19 | (1) |
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20 | (1) |
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20 | (7) |
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Chapter 2 Animal models for preclinical Parkinson's research: An update and critical appraisal |
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27 | (34) |
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28 | (1) |
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2 Models in different species |
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28 | (1) |
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3 The importance of nigrostriatal dopaminergic degeneration |
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29 | (1) |
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30 | (2) |
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5 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) |
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32 | (1) |
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6 Environmental toxicants |
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33 | (2) |
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33 | (1) |
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34 | (1) |
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35 | (1) |
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36 | (9) |
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8.1 The AAV-&alplha;-synuclein model |
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36 | (2) |
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8.2 The PFF inoculation model |
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38 | (3) |
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8.3 Combined AAV-PFF α-synuclein models |
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41 | (1) |
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8.4 Transgenic α-synuclein overexpressing mice |
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42 | (3) |
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9 Other genetic models of PD |
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45 | (2) |
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47 | (1) |
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48 | (1) |
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48 | (13) |
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Chapter 3 Selective neuronal vulnerability in Parkinson's disease |
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61 | (30) |
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Patricia Gonzalez-Rodriguez |
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62 | (1) |
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2 Cell autonomous determinants of vulnerability |
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63 | (5) |
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3 Non-cell autonomous determinants and ct-SYN |
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68 | (3) |
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4 Toward a consensus view of PD pathogenesis |
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71 | (2) |
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73 | (18) |
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Chapter 4 Mechanisms of alpha-synuclein toxicity: An update and outlook |
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91 | (40) |
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93 | (2) |
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2 Parkinson's disease: Clinical features and genetic factors |
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95 | (1) |
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3 Other synucleinopathies |
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96 | (1) |
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3.1 Dementia with Lewy bodies |
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96 | (1) |
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3.2 Multiple system atrophy |
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96 | (1) |
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3.3 Pure autonomic failure |
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97 | (1) |
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3.4 REM sleep behavior disorder |
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97 | (1) |
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3.5 Genetic factors in other synucleinopathies |
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97 | (1) |
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97 | (5) |
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4.1 Alpha-synuclein physiology |
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97 | (1) |
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98 | (2) |
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4.3 Tertiary and quaternary structure of aSyn |
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100 | (1) |
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4.4 The effect of PD-associated mutations in aSyn |
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101 | (1) |
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4.5 Post-translational modifications |
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101 | (1) |
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5 Alpha-synuclein pathology in the synapse |
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102 | (1) |
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6 aSyn pathology in mitochondria |
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103 | (1) |
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7 aSyn pathology in the ER-Golgi compartments |
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104 | (3) |
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7.1 Degradation and clearance of aSyn |
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105 | (1) |
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7.2 aSyn pathology and the cytoskeleton |
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106 | (1) |
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7.3 Effects of aSyn in the nucleus |
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106 | (1) |
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8 Spreading of aSyn pathology |
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107 | (3) |
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9 The interplay between aSyn and the microbiome |
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110 | (1) |
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110 | (1) |
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11 Conclusions and outlook |
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111 | (1) |
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112 | (1) |
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112 | (19) |
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Chapter 5 The role of glia in Parkinson's disease: Emerging concepts and therapeutic applications |
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131 | (38) |
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1 Glial cells in PD: A brief introduction |
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132 | (6) |
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1.1 Physiopathological functions of microglia |
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133 | (3) |
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1.2 Physiopathological functions of astroglia |
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136 | (2) |
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2 Role of glia in the neurodegenerative process |
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138 | (4) |
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138 | (2) |
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140 | (2) |
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3 Role of glia in dopamine replacement therapy |
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142 | (3) |
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3.1 Role of glia in the uptake and metabolism of L-DOPA |
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142 | (1) |
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3.2 Role of glia in L-DOPA-induced dyskinesia |
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143 | (1) |
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3.3 Gliovascular mechanisms in L-DOPA-induced dyskinesia |
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144 | (1) |
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4 Therapeutic applications |
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145 | (7) |
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4.1 Microglia as a therapeutic target for disease-modification |
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145 | (4) |
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4.2 Astroglia as an effector of disease-modifying treatments |
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149 | (1) |
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4.3 Glial-based cell replacement therapies for PD |
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150 | (1) |
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4.4 Targeting glial mechanisms to treat L-DOPA-induced dyskinesia |
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151 | (1) |
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152 | (1) |
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152 | (17) |
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Chapter 6 Innate and adaptive immune responses in Parkinson's disease |
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169 | (48) |
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169 | (2) |
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2 PD as a systemic and heterogeneous disease |
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171 | (1) |
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172 | (3) |
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175 | (3) |
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5 CNS inflammation in human PD |
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178 | (3) |
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178 | (2) |
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180 | (1) |
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6 Peripheral inflammation in PD |
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181 | (3) |
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181 | (2) |
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6.2 Gastrointestinal tract, enteric nervous system, and the microbiome |
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183 | (1) |
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7 The immuno-genetics of PD |
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184 | (3) |
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184 | (1) |
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185 | (1) |
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185 | (1) |
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186 | (1) |
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8 Immune modulation and risk of Parkinson's disease |
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187 | (1) |
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9 Inflammation in murine models of PD |
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187 | (6) |
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9.1 Neurotoxin-based animal models of PD |
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188 | (2) |
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9.2 α-syn based animal models of PD |
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190 | (3) |
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10 Conclusions and key questions |
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193 | (6) |
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10.1 Key question 1: What is the role of a-syn in activating the immune system? |
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193 | (3) |
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10.2 Key question 2: Is Parkinson's disease caused by an immune response that originates in the gut? |
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196 | (1) |
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10.3 Key question 3: What is the role of microglia in Parkinson's disease? |
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197 | (1) |
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10.4 Key question 4: How do t cells contribute to the pathobiology of Parkinson's disease? |
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198 | (1) |
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199 | (1) |
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199 | (18) |
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Chapter 7 Pathways of protein synthesis and degradation in PD pathogenesis |
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217 | (54) |
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217 | (1) |
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218 | (8) |
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218 | (3) |
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221 | (3) |
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2.3 Post-translational modification |
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224 | (2) |
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226 | (16) |
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226 | (5) |
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231 | (6) |
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3.3 Endoplasmic reticulum |
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237 | (5) |
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242 | (1) |
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242 | (1) |
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242 | (29) |
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Chapter 8 Endosomal sorting pathways in the pathogenesis of Parkinson's disease |
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271 | (36) |
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1 Genetics lead the way to understanding Parkinson's disease pathogenesis |
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272 | (1) |
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2 Role of familial PD genes in endosomal sorting pathways |
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273 | (12) |
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2.1 The endolysosomal system |
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273 | (2) |
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2.2 Vacuolar protein sorting-associated protein 35 (VPS35) |
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275 | (4) |
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2.3 Leucine-rich repeat kinase 2 (LRRK2) |
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279 | (4) |
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283 | (2) |
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3 Emerging endosomal evidence in PD: Synaptic vesicle endocytosis and Rab GTPases |
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285 | (5) |
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3.1 Synaptic vesicle endocytosis (SVE) |
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285 | (3) |
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288 | (2) |
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4 Conclusion and future directions |
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290 | (1) |
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291 | (1) |
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291 | (16) |
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Chapter 9 New players in basal ganglia dysfunction in Parkinson's disease |
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307 | (22) |
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307 | (1) |
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308 | (2) |
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2.1 Stimulation of the spinal cord |
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308 | (2) |
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3 The pedunculopontine nucleus |
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310 | (1) |
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3.1 Stimulation of the pedunculopontine nucleus area |
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311 | (1) |
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4 The substantia nigra pars reticulata |
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311 | (1) |
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4.1 Stimulation of the substantia nigra pars reticulata |
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311 | (1) |
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312 | (2) |
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6 The superior colliculus |
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314 | (1) |
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315 | (1) |
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8 The parabrachialis nucleus |
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316 | (1) |
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9 The nucleus basalis of Meynert |
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316 | (1) |
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9.1 Stimulation of the nucleus basalis of Meynert |
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317 | (1) |
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317 | (1) |
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318 | (11) |
Part II Translational therapeutics |
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Chapter 10 Prodromal PD: A new nosological entity |
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329 | (28) |
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331 | (1) |
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2 Pathophysiology: Current concepts |
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332 | (1) |
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333 | (12) |
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3.1 The research criteria for prodromal PD |
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334 | (1) |
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335 | (3) |
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338 | (7) |
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345 | (1) |
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346 | (11) |
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Chapter 11 The gut microbiome in Parkinson's disease: A culprit or a bystander? |
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357 | (94) |
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1 Gut microbiota in healthy subjects |
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358 | (8) |
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1.1 Introductions and definitions |
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358 | (1) |
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1.2 Microbial diversity: Definition and significance |
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359 | (3) |
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1.3 Factors modulating gut microbiota |
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362 | (3) |
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1.4 "Microbiota for dummies": Disentangling methods for studying gut microbiota |
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365 | (1) |
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2 Gut microbiota in the pathogenesis of Parkinson's disease |
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366 | (11) |
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2.1 Gut microbiota and neuroinflammation |
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367 | (4) |
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2.2 Metabolic mediators: The role of SCFAs in PD |
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371 | (3) |
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2.3 Is PD associated with a "leaky gut"? |
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374 | (3) |
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2.4 The role of virus (phageome) |
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377 | (1) |
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377 | (4) |
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377 | (1) |
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3.2 PD-causing genes and neuroinflammation |
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378 | (3) |
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3.3 Genes involved in the modulation of immune response to microbiota |
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381 | (1) |
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4 Environmental factors/lifestyle habits modulating gut microbiota |
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381 | (4) |
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4.1 Environmental factors |
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381 | (2) |
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383 | (2) |
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5 Upper gut microbiota (nasal, stomach and small intestine) and PD |
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385 | (1) |
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5.1 Nasal and oral microbiota |
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385 | (1) |
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5.2 Stomach: Helicobacter pylori and response to Levodopa |
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385 | (1) |
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5.3 Small intestine: The role of bacterial overgrowth (SIB0) |
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386 | (1) |
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6 Lower gut microbiota (colonic) and PD |
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386 | (34) |
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386 | (12) |
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398 | (22) |
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7 Are gut microbiota changes a cause or a consequence of Parkinson's disease? |
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420 | (3) |
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7.1 Relationship between gut microbiota and PD clinical features |
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421 | (1) |
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7.2 Interaction between gut microbiota and PD medications |
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421 | (2) |
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8 Interventions on gut microbiota as potential disease modifying strategies? |
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423 | (1) |
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9 Does PD start in the gut? |
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424 | (3) |
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9.1 A pathogen passes the gastrointestinal mucosa |
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425 | (1) |
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9.2 a-Syn aggregates in post-ganglionic ENS terminals |
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425 | (1) |
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9.3 Does a-syn pathology spread from gut to brain? |
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425 | (2) |
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9.4 How does a-syn spread throughout the CNS? |
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427 | (1) |
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9.5 Do Lewy bodies induce neuronal death? |
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427 | (1) |
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427 | (1) |
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428 | (1) |
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428 | (19) |
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447 | (4) |
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Chapter 12 Novel approaches to counter protein aggregation pathology in Parkinson's disease |
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451 | (42) |
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451 | (4) |
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455 | (4) |
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2.1 Immunotherapy-Passive |
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456 | (2) |
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458 | (1) |
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3 Small molecule anti-aggregates |
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459 | (2) |
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4 Lysosomal-based enhancers |
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461 | (3) |
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464 | (2) |
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466 | (1) |
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467 | (1) |
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468 | (1) |
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9 Preclinical developments |
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469 | (3) |
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9.1 β2-adrenergic receptor agonists |
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469 | (1) |
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470 | (1) |
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470 | (1) |
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9.4 Stearoyl-CoA desaturase inhibition |
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471 | (1) |
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9.5 Inflammasome inhibition |
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471 | (1) |
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9.6 Proteasome activation |
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472 | (1) |
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9.7 Deubiquitinating enzymes |
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472 | (1) |
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472 | (2) |
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474 | (1) |
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474 | (1) |
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474 | (19) |
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Chapter 13 Repurposing anti-diabetic drugs for the treatment of Parkinson's disease: Rationale and clinical experience |
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493 | (32) |
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1 Links between diabetes and Parkinson's disease |
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494 | (2) |
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2 Causation or shared patho-etiology? |
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496 | (3) |
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499 | (1) |
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499 | (1) |
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5 Thiozolidinediones and PD |
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500 | (1) |
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6 Insulin as a therapy for PD |
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501 | (1) |
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7 GLP-1 receptor agonists, DPP-4 inhibitors and PD |
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502 | (11) |
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7.1 DPP4 inhibitors and PD |
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502 | (1) |
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503 | (1) |
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7.3 The rationale for using GLP-1 receptor agonists in PD |
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504 | (1) |
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504 | (1) |
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7.5 GLP-1 in animal models |
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505 | (1) |
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7.6 Results of exenatide in clinical trials |
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506 | (7) |
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8 Which PD patients might do best on GLP-1 agonist medications? |
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513 | (1) |
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8.1 Dual incretin agonists |
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513 | (1) |
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514 | (1) |
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514 | (11) |
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Chapter 14 Basal ganglia oscillations as biomarkers for targeting circuit dysfunction in Parkinson's disease |
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525 | |
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526 | (4) |
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1.1 Why circuit level pathophysiological processes are important to consider in PD |
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526 | (2) |
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1.2 The emergence and spreading of synchronized oscillatory activity in cortico-basal ganglia-thalamic structures in PD |
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528 | (1) |
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1.3 The value of translational neurophysiological biomarkers for improved treatment of PD |
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529 | (1) |
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2 Oscillations associated with hypokinesia |
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530 | (5) |
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2.1 Recordings in PD patients |
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530 | (1) |
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2.2 Recordings in primate models of PD |
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531 | (1) |
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2.3 Recordings in rodent models of PD |
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532 | (1) |
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2.4 Beta oscillations in neuronal networks and the role abnormal connectivity |
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533 | (1) |
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2.5 Utilizing beta activity for target selection and programming in DBS |
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534 | (1) |
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3 Oscillations related to hyperkinesia |
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535 | (4) |
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3.1 Oscillations associated with dystonia |
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535 | (1) |
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3.2 Oscillations associated with dyskinesia |
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536 | (3) |
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4 Oscillations at very high frequencies (>100Hz) |
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539 | (1) |
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5 Oscillations associated with non-motor symptoms |
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540 | (1) |
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6 Oscillations as biomarkers for targeting circuit dysfunction |
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541 | (3) |
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6.1 Oscillations as biomarkers in neuromodulation |
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541 | (2) |
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6.2 Oscillations as biomarkers in drug development |
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543 | (1) |
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544 | (1) |
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544 | |