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筋萎縮性側索硬化症における上位運動ニューロン障害の神経生理学的指標に関する研究

大塚, 十里 東京大学 DOI:10.15083/0002006961

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名大塚十里
本研究は筋萎縮性側索硬化症の上位運動ニューロン障害を、客観的な指標を用いて評価す
ることを試みたものであり、下記の結果を得ている。
1. 上位運動ニューロンの客観的な評価方法の一つに、経頭蓋磁気刺激における中枢運動伝
導時間 (CMCT) があり、筋萎縮性側索硬化症 (ALS) では CMCT が異常となることが報
告されていることから、ALS と似た経過で上位運動ニューロン徴候を呈する多系統萎縮症
(MSA) を対照群におき、多数の症例を用いて後方視的に評価した。MSA では上位運動ニュ
ーロン障害を呈するにも関わらず四肢における CMCT は正常範囲内であった。ALS では、
一定の頻度で上肢・下肢ともに中枢運動伝導時間の延長や運動誘発電位導出不能が認めら
れた。ALS におけるこれらの異常は、臨床的な上位運動ニューロン徴候と相関する指標に
なり得るとともに、臨床徴候で覚知できる前の段階の錐体路異常を反映する指標、加えて下
位運動ニューロン障害が優位となり上位運動ニューロン徴候を評価できない場合の錐体路
異常を反映する指標にもなり得ることが示唆された。
2. ALS の上位運動ニューロン障害の評価方法の候補として、CMCT の他に「短潜時皮質
内抑制 (SICI) の減少」があることが知られている。この SICI を評価する上で必要となる
安静時運動閾値 (RMT) を評価するために、閾値推定法を組み入れ、測定を自動化したプロ
グラムを作成した。健常者 53 人において、このプログラムで、単発刺激・二発刺激におけ
る RMT を同日に 2 回、別日に 2 回の計 4 回測定した。二発刺激の各刺激間間隔における
RMT と単発刺激における RMT の差分を増減率として算出し、閾値が増加した場合を SICI
が認められると評価した。RMT と増減率の再現性の評価には級内相関係数を使用した。健
常者において、このプログラムを用いて測定した RMT は同日・別日のいずれの施行におい
ても、単発刺激・二発刺激に関わらず高い再現性を示した。一方で、閾値の増減率は、同日・
別日ともに級内相関係数の値は低くなった。これには級内相関係数の統計学的な性質によ
る影響もあると考えられた。検査手法の改善・検討課題として、刺激間間隔の項目数を増や
す、target amplitude の最適化を図ることが必要であると思われた。
3. ALS において、このプログラムを用いて、単発刺激・二発刺激の RMT を測定し SICI
を評価した。本研究において、健常者と比較して ALS では有意に SICI が減弱していると
いう結果であった。しかし既報告よりも感度・特異度ともに低かった。その理由として、本
研究における ALS 患者群は SICI が減弱している群と SICI が正常に認められる群の二峰
性になることが分かり、そのため感度・特異度が既報告より劣ったのではないかと推察され

た。SICI が正常に認められる群の SICI や臨床徴候を経時的に評価することが今後の課題
と考えられた。
4. ALS において一定の頻度で MEP が導出できない症例があり、それらの症例に対して、
同じ刺激強度の刺激を短い刺激間間隔で連発させることで MEP を導出させることに成功
した。
以上、本論文は筋萎縮性側索硬化症の上位運動ニューロン障害の客観的な評価として
CMCT 異常、SICI の減少といったパラメータが有用であることを示した。また CMCT の
錐体路の評価における新たな可能性を見出せ、連発刺激といった新しい刺激手法を同定す
ることができ、今後の経頭蓋磁気刺激の臨床応用において重要な知見が得られたものと考
えられ、学位の授与に値するものと考えられる。
よって本論文は博士( 医学 )の学位請求論文として合格と認められる。

この論文で使われている画像

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152

ADM

abductor digiti minimi

小指外転筋

AE-COPD

acute exacerbation of chronic obstructive

慢性閉塞性肺疾患の急性増悪

pulmonary disease

ALS

amyotrophic lateral sclerosis

筋萎縮性側索硬化症

ALSFRS

Amyotrophic Lateral Sclerosis Functional Rating Scale

AMT

active motor threshold

活動時運動閾値

ANOVA

analysis of variance

分散分析

ATR

Achilles tendon reflex

アキレス腱反射

AUC

area under the curve

BB/Bi

Biceps brachii

BI

Barthel Index

BrTR

brachioradial tendon reflex

腕橈骨筋腱反射

BTR

biceps tendon reflex

上腕二頭筋腱反射

CMCT

central motor conduction time

中枢運動伝導時間

CS

conditioning stimulation

条件刺激

CSP

cortical silent period

皮質サイレントピリオド

Del

deltoid

三角筋

EAAT2

excitatory amino acid transporter 2

興奮性アミノ酸トランスポータ

上腕二頭筋

ー2

ECR

extensor carpi radialis

橈側手根伸筋

EHI

Edinburgh Handedness Inventory

EMG

electromyography

針筋電図

EPSP

excitatory postsynaptic potential

興奮性シナプス後電位

FDI

first dorsal interosseous

第一背側骨間筋

FHB

flexor hallucis brevis

短母指屈筋

FTD

frontotemporal degeneration

前頭側頭変性症

GABA

gamma-aminobutyric acid

γアミノ酪酸

GC

gastrocnemius

腓腹筋

ICC

intraclass correlation coefficient

級内相関係数

ICF

intracortical facilitation

皮質内促通

I/O curve

input-output curve

ISI

interstimulus interval

刺激間間隔

LE

lower extremity

下肢

153

LMN

lower motor neuron

下位運動神経

M1

primary motor area

一次運動野

MEP

motor evoked potential

運動誘発電位

MND

motor neuron disease

運動神経疾患

MRC

Medical Research Council

mRS

modified Rankin Scale

MS

multiple sclerosis

多発性硬化症

MSA

multiple system atrophy

多系統萎縮症

MSO

maximum stimulator output

最大刺激出力

MT

motor threshold

運動閾値

MUP

motor unit potential

運動単位電位

NS

not significant

OP

opponens pollicis

PEST

parameter estimation by sequential testing

PLS

primary lateral sclerosis

原発性側索硬化症

PMA

progressive muscle atrophy

進行性筋萎縮症

ppTMS

paired-pulse paradigm TMS

二発刺激

PTR

patellar tendon reflex

膝蓋腱反射

PV

parvalbumin

Quad

quadriceps femoris

rEEC

revised El Escorial criteria

RMT

resting motor threshold

ROC

receiver operating characteristic

SICF

short-interval intracortical facilitation

短潜時皮質内促通

SICI

short-interval intracortical inhibition

短潜時皮質内抑制

spTMS

single pulse TMS

単発刺激

TA

tibialis anterior

前脛骨筋

TH

threshold hunting

閾値探索

TMS

transcranial magnetic stimulation

経頭蓋磁気刺激

TS

test stimulation

試験刺激

TT

threshold tracking

閾値追跡

TTR

triceps tendon reflex

上腕三頭筋腱反射

UE

upper extremity

上肢

母指対立筋

大腿四頭筋

安静時運動閾値

154

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