76 (4-5): 235 239 (2017) 235 講 演 平成 28 年日本大学医学会秋季学術大会同窓会学術奨励賞受賞講演 -synucleinopathy Ⅰ.α-synucleinopathy? Ⅰ-1.α-synucleinopathy とは -synucleinopathy -synuclein (asyn) 1 Parkinson (Parkinson s disease, PD) (dementia with Lewy bodies, DLB) (Lewy body, LB) (multiple system atrophy) 1 LB (Fig 1a) asyn (Lewy neurite, LN) 1 asyn (Fig 1b) 1 asyn Ⅰ-2. 日本における α-synucleinopathy の現状 -synucleinopathy PD DLB LB MSA /10 PD 164 2 MSA 8 3 synucleinopathy PD PD PD 4 (Fig 2) Alzheimer LB DLB 5 (Fig 3) -synucleinopathy LB PD PD Ⅱ.Parkinson 病の臨床と病理 Ⅱ-1.Parkinson 病の基本的な臨床像 1817 James Parkinson 6 PD An Essay on Shaking Palsy 6 7 Parkinson PD J.-M. Charcot maladie de Parkinson 6 Parkinson s disease Fig. 2 Trends in number of patient with Parkinson s disease in Japan Fig. 1 Lewy body and Lewy neurite in the tissue of a patient with Parkinson s disease (1a, phosphorylated alpha-synuclein), and intracytoplasmic inclusion and neuronal cytoplasmic inclusion in the tissue of a patient with multiple system atrophy (1b, phosphorylated alpha-synuclein). Fig. 3 Cause of dementia in Japan adapted from Asada 5 28 2016 10 1
236 4 8 9 PD PD 8 Ⅱ-2.Parkinson 病病理の変遷 PD LB 10 2003 2009 Braak Hawkes 11 12 PD asyn LB LB 2 PD PD Uchihara 13 asyn LB Ⅲ.Parkinson 病の臨床病理学的検討 Parkinson PD 1 Ⅲ-1. ある Parkinson 病患者の病理解剖症例から 84 3 5 6 LB LN PD PD (Fig 4a, b) LB (pituitary posterior lobe, PPL) (Fig 4c) asyn CA2/3 pasyn (CA2/3 phosphorylated asyn-neurite) (Fig 4d) (transentorhinal spongiform change, TER SpC) (Fig 4e) DLB 14 (argyrophilic grain, ArG) (Fig 4f) Fig. 4 Depigmented substantia nigra was observed in the midbrain of a patient with Parkinson s disease (4a). Microscopically, Lewy body was seen in the substantia nigra (4b, Hematoxylin & eosin). Sagittal section of the pituitary gland; PAL, pituitary anterior lobe; PPL, pituitary posterior lobe (4c-left, Hematoxylin & eosin). Phosphorylated alpha-synuclein-positive neurite (red arrow) and dots (yellow arrow) were in the PPL (4c-right, phosphorylated alpha-synuclein). Phosphorylated alpha-synuclein-positive neurite in the CA 2/3 (4d, phosphorylated alpha-synuclein), spongiform change of the transentorhinal cortex (4e, Hematoxylin & eosin), and argyrophiclic grain in the ambient gyrus (4f, Gallyas-Braak stain).
76 (4-5) 2017 -synucleinopathy 237 (argyrophilic grain dementia, AGD) 15 PD asyn LB DLB AGD PD Ⅲ-2.Parkinson 病に関する病理学的 臨床病理学的検討 -2a PPL Lewy 16 PPL pasyn LB 60 PD, 23 ; DLB, 1 ; MSA, 9 ; 10 ;, 3 ; 1 ; AGD, 1 ; 1 ; 2 ; 5 ; 1 ; 1 ;, 1 ; 1 Hoehn-Yahr stage Braak PD stage 11 1 PPL pasyn 2 PPL paraventricular nucleus, PVN (supraoptic nucleus, SON) pasyn LB Table 1 LB pasyn PPL (95.8%) non-lb (8.3%) (P < 0.0001) alphasynucleinopathy PPL pasyn PD 95.7% PPL pasyn MSA 11.1% (P < 0.0001) asyn PPL pasyn PD DLB LB 88.5%; 97.1% PPL PVN SON pasyn (neuropil) LB asyn -2b. Parkinson 17 PD PD PD ArG TER SpC CA2/3 pasyn-neurite (PD with dementia, PDD) DLB 20 PD 8 PD without dementia (PDND), 8 ; PDD, 12 Braak PD stage Braak neurofibrillary tangle stage 18 Braak senile plaque stage 18 ArG TER SpC CA2/3-paSyn-neurite scoring system PD ArG TER SpC CA2/3 pasyn neurite Table 2 PD ArG (P=0.0021) PDND PDD SpC (P=0.0193) 3 ArG TER SpC CA2/3 pasyn neurite PDD 3 Table 1 Clinical and neuropathological data relating to the studied cases Table 1. Clinical and neuropathological data adapted relating from to Homma the studied T et al 16 cases Case No Male:Female ratio Age at death (years) Brain weight (g) Positive case of pasyn IHC in PPL (mean (SD)) (mean (SD)) (%) LB-related disorder 24 13:11 75.3 (5.21) 1255 (118.4) 23/24 (95.8) Non-LB-related disorder 36 24:12 68.1 (13.1) 1255 (148.8) 3/36 (8.3) pasyn, phosphorylated alpha-synuclein; IHC, immunohistochemistory; PPL, pituitary posterior lobe; LB, Lewy body
238 Table 2 Distribution and degree of argyrophilic grain, spongiform change of the transentorhinal cortex and phosphorylated alpha-synucleinpositive neurite in the CA2/3 among 20 PD cases adapted from Homma T et al 17 Table 2. Distribution and degree of argyrophilic grain, spongiform change of transentorhinal cortex and phosphorylated alpha-synuclein-positive neurite in CA2/3 among 20 PD cases ArG score in Medial temporal region TER SpC score CA2/3 pasyn neurite score Anterior Posterior Total Total ArG score Ant Post Case No Amy Amb ER TER ER TER Subic CA1 TER SpC score PDND 8 0.13 0.25 0.13 0.13 0.00 0.00 0.00 0.00 0.63 0.13 0.00 0.13 0.88 PDD 12 1.25 1.42 1.25 1.17 0.58 0.58 1.50 0.83 8.58 1.25 0.83 2.08 1.58 PDD-ArG 5 2.00 2.40 1.80 2.00 1.00 1.20 2.80 1.60 14.8 0.40 0.00 0.40 1.00 PDD-TER SpC 5 0.80 0.80 0.80 0.60 0.40 0.20 0.40 0.20 4.20 2.40 2.00 4.40 2.20 PDD-NOS 2 0.50 0.50 1.00 0.50 0.00 0.00 1.00 0.50 4.00 0.50 0.00 0.50 1.50 PDND, Parkinson's disease without dementia; PDD, Parkinson's disease with dementia; ArG, argyrophilic grain; TER SpC, spongiform change in the transentorhinal cortex, NOS, not otherwise specified Amy, amygdala; Amb, ambient gyrus; ER, entorhinal gyrus; TER, transentorhinal gyrus; Subic, subiculum; ArG, argyrophilic grain; SpC, spongiform change; pasyn, phosphorylated alpha-synuclein ArG PDD (PDD-ArG) PDD (PDD-TER SpC) 2 PDD Ⅳ. まとめ - これまでの Parkinson 病研究で知り得た結果と今後の検討課題 - PD -2. PD DLB 1 LB PD 2 PD LB 3 PDD DLB DLB 10) 2007;25:37-40 11) Braak H, Del Tredici K, Rub U, de Vos RAI, Steur ENHJ, Braak E. Staging of brain pathology related to sporadic Parkinson s disease. Neurbiology of Aging 2003;24:197-211 12) Hawkes CH, Del Tredici K, Braak H. Parkinson s disease: The dual hit theory revisited. Ann N.Y. Acad Sci. 2009;1170:615-622 13) Uchihara T, Giasson BI, Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol. 2016;131:49-73 14) McKeith IG, Galasko D, Kosaka K et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 1996;47:1113-1124 15) Tolnay M, Clavaguera F. Argyrophilic grain disease: A lateonset dementia with distinctive features among tauopathies. Neuropathology 2004;24:269-283 16) Homma T, Mochizuki Y, Mizutani T. Phosphorylated -synuclein immunoreactivity in the posterior pituitary lobe. Neuropathology. 2012;32:385-389 17) Homma T, Mochizuki Y, Takahashi K, Komori T. Medial temporal regional argyrophilic grain as a possible important factor affecting dementia in Parkinson s disease. Neuropathology. 2015;35:441-451 18) Braak H, Braak E. Neuropathological staging of Alzheimerrelated changes. Acta Neuropathol 1991;82:239-259. 文 献 1) 2015;33:273-282 2) 2009;98:57-66 3) 1989;29:164-166 4) 26 (2014) 5) : 2012;52:962-964 6) Donaldson IM. James Parkinson s essay on the shaking palsy. J R Coll Physicians Edinb. 2015;45:84-86 7) 100 Brain and Nerve 2012;64:474-485 8) 2016: p16-p21 9) 2007;25:43-45
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