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A B C - The Movement Disorder Society
家族性パーキンソン病患者の心筋における 123I-MIBG
の取り込み
Myocardial 123Metaiodobenzylguanidine Uptake in Genetic Parkinson’s Disease
*, **
Aldo Quattrone, MD, Antonio Bagnato, MD, Grazia Annesi, PhD, Fabiana Novellino, MD, Letterio Morgante,
MD, Giovanni Savettieri, MD, Mario Zappia, MD, Patrizia Tarantino, PhD, Innocenza Claudia Cirò Candiano, PhD,
Ferdinanda Annesi, PhD, Donatella Civitelli, PhD, Francesca Emanuela Rocca, PhD, Marco D’Amelio, MD, Giuseppe
Nicoletti, MD, Maurizio Morelli, MD, Alfredo Petrone MD, Piercostanzo Loizzo, MD, and Francesca Condino, PhD
*
Institute of Neurology, University Magna Graecia, Catanzaro, Italy
Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, Italy
*
*
123
I-metaiodobenzylguanidine(MIBG)心筋シンチグ
変異を伴う非血縁患者 6 例中 3 例では心筋 MIBG 取り
ラフィーは,心臓交感神経の節後線維の評価に利用でき
込みが保たれていたのに対し,弧発性 PD 患者の全例で
る。パーキンソン病(Parkinson’
s disease; PD)患者
MIBG 取り込みは低下していた。対照被験者の MIBG 取
では,ほぼ全例で MIBG の取り込みが低下している。本
り込みはいずれも正常であった。今回の研究において心
研究の目的は,家族性 PD 患者における MIBG 取り込み
筋 MIBG 取り込みは家族性 PD 患者 14 例中 8 例で正
を評価することである。様々な遺伝子変異〔Parkin ,
常であったことから,家族性 PD では弧発性 PD に比べ
DJ-1,PINK1,leucine-rich repeat kinase 2(LRRK2 )
〕
心臓交感神経の脱神経の発現頻度が低いことが示唆さ
を伴う PD 患者 14 例,弧発性 PD 患者 15 例,対照被
れる。また,今回の知見から,同一遺伝子に異なる変異
験者 10 例を対象に MIBG の取り込みを検討した。Par-
を伴う患者,あるいは同じ遺伝子変異を伴う患者であっ
kin 変異を伴うパーキンソン症候群患者 4 例中 3 例,
ても,神経障害には差があり,家族性 PD における
DJ-1 変異を伴う患者 2 例中 1 例,PINK1 変異を伴う兄
MIBG 取り込みパターンは一様でないことも明らかに
弟の患者 2 例中 1 例,LRRK2 遺伝子に Gly2019Ser
なった。
Movement Disorders Vol. 23, No. 1, 2008, pp. 21-27
Key Word 心筋シンチグラフィー,家族性 PD
パーキンソン病(Parkinson’s disease; PD)患者では運
核上性麻痺患者の MIBG 取り込みは,PD 患者とは異な
動症状以外に自律神経障害も報告されている。最近いく
り正常であることが報告されている。このことから,心
つかの研究で PD 患者の交感神経終末の評価における
筋シンチグラフィーが PD とこれらのパーキンソン症候
123
I-metaiodobenzylguanidine(MIBG)心筋シンチグラ
群の鑑別に有用である可能性が示唆される 4-6,8。最近の
フィーの有用性が検証されており,ほぼすべての PD 患
研究では,Parkin 遺伝子変異を伴う早期発症 PD(early-
者で MIBG 取り込み低下が認められている 。MIBG 取
onset PD; EOPD)
患者 4 例の MIBG 取り込みは正常であっ
り込み低下は心臓交感神経の脱神経を示唆する所見であ
たのに対し 9,10,α -synuclein 遺伝子変異を伴う EOPD 患
り,非常に初期の PD 患者や明らかな自律神経障害のな
者では取り込みが低下していることが報告された 11。本
い PD 患者でもこの所見が認められることから,節後線
研究では,Parkin,DJ-1,PINK1,leucine-rich repeat
維の障害が PD 初期から生じている可能性が考えられ
kinase 2(LRRK2)の各遺伝子に変異を伴う PD 患者を対
る 。別の複数の研究では,多系統萎縮症および進行性
象に,MIBG 心筋シンチグラフィーを実施した。
1-4
6,7
2
A. Quattrone et al.
対象および方法
本研究は家族性 PD 患者 14 例,弧発性 PD 患者 15 例,
取り込みを測定して心筋/縦隔(heart/mediastinum; H/M)
比を計算した。被験者全例の早期像および後期像から求
めた H/M 比を評価し,H/M 比が各対照平均値よりも 3
対照被験者 10 例を対象とした。家族性 PD 患者では,14
標準偏差(standard deviation; SD)以上下回った場合を異
例中 4 例(うち 2 例は同胞)が Parkin 変異,非血縁患者
常値とみなした。局所の MIBG 取り込みは,
3 軸断層像
(短
2 例が DJ-1 変異,2 例(兄弟)が PINK1 変異,6 例(1
軸断層像,垂直面長軸断層像,水平面長軸断層像)によ
例は家族歴あり,5 例はおそらく孤発例)が LRRK2 遺伝
る SPECT で評価した。画像評価は,患者の診断につい
子の Gly2019Ser 変異を伴っていた。弧発性 PD 患者では,
て盲検化された研究者 1 名が行った。
LRRK2 遺伝子の Gly2019Ser および Ile2020Thr 変異は陰
性であった。PD の診断は UK Parkinson’s Disease Society
遺伝子検査
Brain Bank の基準に従って行った。すべての患者におい
遺伝子解析用の血液試料は,すべての患者および対照
て薬効 off 期(一晩薬剤投与を行わない)に Unified
被験者からインフォームドコンセントを得た後,採取し
(運動)
Parkinson’s Disease Rating Scale(UPDRS)PartⅠ
Ⅰ
Ⅰ
た。DNA は 標 準 法 で 調 製した。患 者 14 例の Parkin,
のスコアと Hoehn and Yahr(HY)分類の評価を行った。
DJ-1 および PINK1 変異と,患者 29 例の LRRK2 遺伝子
全例で自律神経系の検査を行った。手関節部の正中神経
の Gly2019Ser および Ile2020Thr 変異を解析した。シーク
に電気刺激を加え,手掌部表面の交感神経皮膚反応を記
エンス解析のため,イントロン配列プライマーを用いて
録した。また,呼吸変化に対する心拍数の反応試験(深
Parkin,DJ-1,PINK1 のコーディング領域および LRRK2
呼吸試験)と起立性低血圧に関する起立試験も,既報の
遺伝子のエクソン 41 をポリメラーゼ連鎖反応(PCR)で
ように実施した 。レボドパ(L—ドパ)+ドパ脱炭酸酵
増幅した。ジデオキシ・サイクルシークエンスは,ABI
素阻害薬は全例で投与され,ドパミンアゴニストは併用
PRISM シークエンシングキットを用いて製造者のプロト
されている場合とされていない場合があった(家族性 PD
コルに従って実施した。続いて,ABI 3130-XL Avant 自動
患者 14 例中 4 例および弧発性 PD 患者 15 例中 5 例はド
DNA シークエンス解析装置を用いてエクソンのシークエ
パミンアゴニスト併用,家族性 PD 患者 1 例はアマンタ
ンスを行った。
12
ジン併用)
。脳 MRI 検査では全例正常であった。本研究
には健常被験者 10 例も参加した。患者および対照被験
統計解析
者の除外基準は,糖尿病,ニューロパチーの病歴,関連
弧発性 PD 患者,家族性 PD 患者,対照被験者間にお
のある心疾患の既往歴,自律神経系または心筋 MIBG 取
ける連続変数(平均年齢および H/M 比)の差は一元配置
り込みに影響しうる PD 以外の病態がある場合とした。
分 散 分 析 で 検 討した後,対 応のない t 検 定を用いて
どの被験者も,交感神経終末の MIBG 取り込みを妨げる
Bonferroni の補正による多重比較を行った。性別分布の
薬物は使用していなかった。本研究に参加する各被験者
群間比較にはカイ二乗検定を用いた。弧発性 PD 群およ
から文書によるインフォームドコンセントを取得した。
び家族性 PD 群間における HY scale のスコアと UPDRS
PartⅠ
Ⅰ
Ⅰ
(運動)のスコアの差は Mann-Whitney U 検定で評
MIBG シンチグラフィー
価し,発症年齢と L—ドパ用量は対応のない t 検定で解析
心筋 MIBG シンチグラフィーは安静時に行った。計
した。H/M 比が低い家族性 PD 患者と H/M 比が正常な
111 MBq の 123I-MIBG(Amersham, Eindhoven, NL)を 60
家族性 PD 患者の比較にも,Mann-Whitney U 検定および
秒かけて静注した。データは,アイソトープ注入 10 分後
対応のない t 検定を用いた。
(早期像)および 240 分後(後期像)にデュアルヘッドガ
ンマカメラ(Axis, Picker, Bedford, OH)にて収集した。
結 果
静止平面像および局所 MIBG 取り込みはマトリクスサイ
ズ 128 × 128 で求めた。定量的な評価には胸部前面像の
PD 患者および対照被験者の特性を Table 1 と 2 に示す。
みを用いた。前面像の心臓全体および縦隔に関心領域
PD 患者(家族性および弧発性)はいずれも L—ドパに良
(region of interest; ROI)を設定し,各 ROI 内のトレーサ
好な反応を示した。家族性 PD 患者では 1 例(LRRK2 変
3
123
MYOCARDIAL123I-MIBG
METAIODOBENZYLGUANIDINE
家族性パーキンソン病患者の心筋における
の取り込み
UPTAKE IN GENETIC PD
23
TABLE 1. Characteristic and H/M ratio in patients with genetic and idiopathic Parkinson’s disease (PD), and controls
Variables
123
Genetic PD (N 14)
Idiopathic PD (N 15)
Controls (N 10)
P-value
METAIODOBENZYLGUANIDINE
UPTAKE IN GENETIC
23
Mean age SD, yr MYOCARDIAL
58.29 12.46
69.47 6.41
63.10 5.53PD
0.007
Sex (N, % male)
8 (57.1)
9 (60.0)
5 (50.0)
0.883
Mean age SD at onset, yr
41.57 11.99
66.33 6.83
–
0.001
TABLE
Characteristic
andyrH/M ratio16.80
in patients
and idiopathic
Parkinson’s disease (PD),
and controls
Duration
of the1.disease,
mean SD,
11.90with genetic 3.13
3.64
–
0.001
Hoehn–Yahr median (range)
2.5 (2-4)
2.0 (1-4)
–
0.001
Variables
Genetic
(N 14)
Idiopathic
PD (N 15)
Controls (N
P-value
UPDRS-ME
38.29 PD
14.69
22.93 12.84
– 10)
0.001
Dosage
566.07
166.30
426.67
237.45
0.08
Mean
ageoflevodopa
SD, yr (mg/daily, mean SD)
58.29
12.46
69.47
6.41
63.10 5.53–
0.007
H/M(N,
ratio
mean SD (range)
Sex
% male)
8 (57.1)
9 (60.0)
5 (50.0)
0.883
Early
1.45 1.16 1.69 015–(1.47-1.94)
0.001
Mean
ageimage
SD at onset, yr
41.57
0.30
11.99(1.13-2.0)
66.33
0.02
6.83 (1.13-1.19)
0.001
Delayed
1.61 1.173.64
0.02 (1.13-1.19)
1.98 0.06– (1.91-2.07)
0.001
Duration
of image
the disease, mean SD, yr
16.80
0.40
11.90(1.13-2.0)
3.13
0.001
Hoehn–Yahr median (range)
2.5 (2-4)
2.0 (1-4)
–
0.001
H/M ratio heart/mediastinum ratio; H/M ratio: genetic PD versus idiopathic PD (early: P 0.001; delayed: P 0.001; unpaired t test corrected
UPDRS-ME
38.29 14.69
22.93 12.84
–
0.001
according to Bonferroni); genetic PD versus controls (early: P 0.003; delayed: P 0.017; unpaired t test corrected according to Bonferroni);
Dosage of levodopa (mg/daily, mean SD)
566.07 166.30
426.67 237.45
–
0.08
idiopathic PD versus controls (P 0.001; delayed: P 0.001, unpaired t test corrected according to Bonferroni).
H/M ratio mean SD (range)
Early image
1.45 0.30 (1.13-2.0)
1.16 0.02 (1.13-1.19)
1.69 015 (1.47-1.94)
0.001
Delayed image
1.61 0.40 (1.13-2.0)
1.17 0.02 (1.13-1.19)
1.98 0.06 (1.91-2.07)
0.001
function (sympathetic skin response absent; deep breatheral sclerosis,13 and two novel DJ-1 mutations, in a
ing test and postural evaluation of blood pressure were
double heterozygous state (g.159 C/G, IVS4 2insA),
according to Bonferroni); genetic PD versus controls (early: P 0.003; delayed:
P 0.017; unpaired
t test corrected according
to Bonferroni);
13
応は陰性,深呼吸試験および起立血圧試験は異常所見)
が認められ,孤発性
EOPD
と思われる
(g.168_185dup)
abnormal),
whereas
dysautonomia
was
never
found
in
in
a patient
with apparently
sporadic EOPD
(Tarantino
P,
idiopathic PD versus controls (P 0.001; delayed: P 0.001, unpaired t test corrected
according
to Bonferroni).
sporadic
PD
patients.
et
al.,
2006;
personal
communication);
a
novel
homozyDJ-1
を示したのに対し,孤発性 PD 患者では自律神経障害は
患者 1 例では複合ヘテロ接合の 2 つの新規
変異
Mutation analyses showed three different mutations in
gous deletion 889delG mutation in the PINK-1 gene in 2
まったく認められなかった。
(g.159
C/G,IVS4+2insA)が認められた(Tarantino
ら,
eral
sclerosis,
function
(sympathetic
skin response
absent;
and two PD
novel
DJ-1
mutations,
a
the Parkin
gene (a homozygous
exon
3deldeep
in a breathsubject
brothers
with 13early-onset
(Cirò
Candiano
IC, etinPal.,
ing
test
and
postural
evaluation
of
blood
pressure
were
double
heterozygous
state
(g.159
C/G,
IVS4
2insA),
遺伝子解析では次の変異が認められた。まず第
1に
2006
信 communication).
)
。 第 3 に,EOPD
患 者 2 analysis
例( 兄 弟
with
apparently sporadic EOPD, a homozygous 2022006;年,私
personal
Mutation
of)の
the
abnormal),
whereas
dysautonomia
was
never found
in
inGly2019Ser
a patient with
apparently
sporadic
EOPDthe
(Tarantino
P,
203delAG
in
another
subject
with
apparently
sporadic
in
the
LRRK2
gene
showed
presence
of
Parkin 遺 伝 子に 3 種 類の 変 異,具 体 的には,孤 発 性
PINK-1 遺伝子に新規のホモ接合欠失変異 889delG が認
sporadic
PD
patients.
et
al.,
2006;
personal
communication);
a
novel
homozyEOPD, and a homozygous exon 3-4del in two siblings
the mutation in a homozygous state in a patient with
EOPD
と思われる被験者
1 例におけるホモ接合のエクソ
められた(Cirò
Candiano
IC ら,2006
。LRRK2
Mutation
analyses
showed
three different
mutations
in
gous
deletion
889delG
in the 年,私信)
PINK-1
gene
2
with
EOPD);
a previously
described
homozygous
mutafamilial
late-onset
PD mutation
(consanguineous
parents,
andindethe
Parkin
gene
(a
homozygous
exon
3del
in
a
subject
brothers
with
early-onset
PD
(Cirò
Candiano
IC,
et
al.,
in exon 7EOPD
(E163K)
and a homozygous1 例におけ
mutation
ceased affected
relatives
in both maternal and parental
ンtion
3del,孤発性
と思われる別の被験者
遺伝子の
Gly2019Ser
に関する変異解析では,家族性の晩
with
apparently in
sporadic
EOPD,region
a homozygous
2022006;
personal
communication).
of the
(g.168_185dup)
the
promoter
of
the
DJ-1
gene
ascendants;
a
living
sibling
withMutation
PD withanalysis
the same
hoるホモ接合の 202-203delAG,EOPD 患者 2 例(同胞)に
期発症 PD 患者 1 例(両親は血族結婚で,母方にも父方
203delAG
in
another
subject
with
apparently
sporadic
Gly2019Ser
in
the
LRRK2
gene
showed
the
presence
in a patient with EOPD, dementia and amyotrophic latmozygous genotype), and the presence of the mutationofin
おけるホモ接合のエクソン
2 に,
にも死亡した罹患者がいる。生存する
名に
EOPD, and a homozygous3-4del
exon が認められた。第
3-4del in two siblings
the
mutation in a homozygous state inPD
a の同胞
patient 1with
with
EOPD);
a
previously
described
homozygous
mutafamilial
late-onset
PD
(consanguineous
parents,
and
deEOPD,認知症および筋萎縮性側索硬化症を伴う患者
1
も同じホモ接合の遺伝子型が認められる)にこのホモ接
2. H/M ratio in patients
with
genetic Parkinson’s disease
tion in exon 7 (E163K) andTABLE
a homozygous
mutation
ceased
affected relatives in both maternal and parental
DJ-1
例
の
遺
伝
子
エ
クソン
7
に
既
報
の
ホ
モ
接
合
変
異
合変異が認められ,孤発性の晩期発症
PDthe
と思われる他
(g.168_185dup) in the promoter region of the DJ-1 gene
ascendants; a living sibling with PD with
same
H/M
ratio hoinGene
a patient with
EOPD,
dementia
and
amyotrophic
latmozygous
genotype),
and
the
presence
of
the
mutation
in
Sex/Age
Onset
H-Y
Therapy (mg/die)
Mutation
Early
Delayed
異を伴う患者
I)のみが自律神経障害(交感神経皮膚反
(E163K)
ロモ
ー タPー
域 unpaired
に ホ モt test
接 corrected
合変異
H/M ratio heart/mediastinum
ratio; H/M ratio: genetic PD versus idiopathic
PD (early: と
P プ0.001;
delayed:
領
0.001;
Parkin
I
II
IIIa
IVa
Gene
DJ-1
Parkin
II
IIII
M/39
M/47
F/54
M/59
Sex/Age
30TABLE 3.0
202-203delAG
hom. disease
2. H/M ratioLD
in 600
patients with genetic
Parkinson’s
37
2.0
LD 500
exon 3del hom.
42
2.0
LD 600b
exon 3-4del hom.
43
2.5
LD 600b
exon 3-4del hom.
Onset
H-Y
Therapy (mg/die)
Mutation
IIIa
PINK-1
a
IV
Ia
a
II
DJ-1
M/47
M/39
M/38
M/47
F/54
M/59
M/74
M/68
38
30
24
37
42
43
29
28
2.5
3.0
3.0
2.0
2.0
2.5
4.0
3.0
LD600
750
LD
LD500
750
LD
LD 600b
LD 600b
LD 500
LD 500
g.159 C/G andhom.
IVS42insA
202-203delAG
g.168_185
dup hom. and E163K hom.
exon
3del hom.
exon 3-4del hom.
exon 3-4del hom.
889delG hom.
889delG hom.
1.45
1.46
1.16
1.73
1.15
1.73
1.18
1.68
1.97
2.0
1.16
1.92
1.15
1.96
1.19
1.93
I
IILRRK2
I
II
PINK-1
IaIII
a
IIIV
V
VI
LRRK2
M/47
M/38
F/74
F/66
F/62
M/74
M/50
M/68
F/68
F/70
38
24
54
53
43
29
42
28
66
53
2.5
3.0
4.0
2.5
3.0
4.0
2.0
3.0
2.0
4.0
LD 750
LD 750
LD 750
LD 500b
LD500
625
LD
LD500
250
LD
LD 250b
LD 750
g.159 C/G and IVS42insA
g.168_185 dup hom. and E163K hom.
Gly2019Ser het.
Gly2019Ser het.
Gly2019Ser
889delG
hom.het
Gly2019Ser
889delG
hom.het
Gly2019Ser het.
Gly2019Ser hom.
1.45
1.16
1.13
1.18
1.15
1.18
1.58
1.68
1.77
2.0
1.97
1.16
1.13
1.19
1.15
1.19
1.97
1.93
1.85
2.0
Gly2019Ser
Gly2019Ser
Gly2019Ser
Gly2019Ser
Gly2019Ser
Gly2019Ser
1.13
1.18
1.15
1.58
1.77
2.0
1.13
1.19
1.15
1.97
1.85
2.0
I a
F/74
54
4.0
LD 750
Siblings; LD levodopa plus dopa decarboxylase inhibitor. b
II b
F/66
53
2.5
LD 500
LD levodopa plus dopa decarboxylase inhibitor and dopamine agonists.
III
F/62
43
3.0
LD 625
H-Y, Hoehn–Yahr; H/M ratio, heart to mediastinum ratio (240 min).
IV
M/50
42
2.0
LD 250
V
F/68
66
2.0
LD 250b
VI
F/70
53
4.0
LD 750
a
Siblings; LD levodopa plus dopa decarboxylase inhibitor.
LD levodopa plus dopa decarboxylase inhibitor and dopamine agonists.
H-Y, Hoehn–Yahr; H/M ratio, heart to mediastinum ratio (240 min).
b
4
1.46
2.0
1.73
1.92
1.15H/M ratio1.15
1.73
1.96
Early
Delayed
het.
het.
het
het
het.
hom.
Movement Disorders, Vol. 23, No. 1, 2008
Movement Disorders, Vol. 23, No. 1, 2008
MYOCARDIAL
MYOCARDIAL
123
METAIODOBENZYLGUANIDINE
123
UPTAKE IN GENETIC PD
METAIODOBENZYLGUANIDINE UPTAKE IN GENETIC PD
A. Quattrone et25
al.
25
FIG. 1. Myocardial 123Metaiodobenzylguanidine (MIBG) planar anterior view and regional radiolabeled MIBGカラー原図をモノクロで掲載しております。
uptake 4 hr p.i., in siblings with
homozygous
exon 3-4123
Parkin
mutations. Planar anterior
view
of theanterior
Parkin-III
(a) showed
severe decrease
cardiac
MIBG
whereas
FIG. 1. Myocardial
Metaiodobenzylguanidine
(MIBG)
planar
viewpatient
and regional
radiolabeled
MIBG of
uptake
4 hr
p.i., uptake,
in siblings
with
MIBG
uptakeexon
was 3-4
normal
in the
Parkin-IV
patient
(b). view
Regional
MIBG
uptakepatient
in the(a)
Parkin-IV
patientdecrease
(c) showed
high MIBG
all the
homozygous
Parkin
mutations.
Planar
anterior
of the
Parkin-III
showed severe
of cardiac
MIBGactivity
uptake,inwhereas
regions
of the heart.
MIBG uptake
was normal in the Parkin-IV patient (b). Regional MIBG uptake in the Parkin-IV patient (c) showed high MIBG activity in all the
regions of the heart.
body pathology itself might cause profound cardiac sympathetic denervation and low MIBG uptake.
pathetic
denervation
and low
MIBG
対照群の
H/M
比(平均±
SD)は早期像で
1.69 ± 0.15,
Our study
also
shows
that
geneticuptake.
PD patients
disOur
study
also
shows
that
genetic
PD
patients
displayed a 1.98
heterogeneous
pattern of cardiac MIBG uptake.
後期像で
± 0.06 であり,正常下限値(平均値から
3
played
a
heterogeneous
pattern
of
cardiac
MIBG
uptake.
Indeed, MIBG uptake varied among PD patients with
SD
を差し引いた値)はそれぞれ
1.23 および
1.81 に設定
Indeed,
MIBG
uptake genes,
varied among
among
PD patients
with
mutations
in different
unrelated
patients
mutations
in
different
genes,
among
unrelated
patients
した。H/M
比は,家族性
PD
群(早期像:1.45
±
0.30,
with different mutations in the same gene (1 of 2 patients
with different
mutationsand
in the
(1 of 2 patients
with
DJ-1 mutations,
1 same
of thegene
4 Parkin-mutated
後期像:1.61
± 0.40,p <
0.001)および対照群(早期像:
with
DJ-1
mutations,
and
1
of
the
4
Parkin-mutated
patients had reduced cardiac MIBG uptake), and also
1.69
± 0.15,後期像:1.98
± 0.06,p
< 0.001)の両者に
patients
had reduced
cardiac
MIBG
andmutaalso
among
unrelated
patients
carrying
the uptake),
same gene
among
unrelated
patients
carrying
the
same
gene
muta比べ,弧発性
PD
群(早期像:1.16
±
0.02,後期像:1.17
tion (3 of 6 patients carrying the Gly2019Ser mutation in
tionLRRK2
(3 of 6 gene
patients
thedecreased
Gly2019Ser
mutation
in
the
hadcarrying
markedly
cardiac
MIBG
±
0.02)で有意に低かった(Table
1)
。いずれの弧発性
the
LRRK2
gene
had
markedly
decreased
cardiac
MIBG
uptake, whereas it was normal in the remaining 3 paPD
患者においても,早期像および後期像の
H/M 比は各
uptake,
whereasresults
it washave
normal
the remaining
3inpatients).
Similar
beeninrecently
reported
5
tients).
Similar
results
have
been
recently
reported
inH/5
patients from three
small families from Japan
with
対照平均値より
3 SD 以上低かった。家族性
PD 群の
patientsmutations.
from three
small
families
fromfrom
Japan
with
19 Two
LRRK2
of these
patients
the same
M
比には対照群との間に有意差が認められた(早期像:
LRRK2
mutations.19 Two of these patients from the same
の
5 例の患者にもヘテロ接合変異が認められた
(Tablesym2)
。
body
pathology itself might cause profound cardiac
p = 0.017,後期像:p = 0.003)
。ただし,家族性 PD 患
者の心筋 MIBG 取り込みパターンは一様ではなかった。
すなわち,14 例中 8 例では MIBG 取り込みが正常であっ
family carrying the Gly2019Ser in the LRRK2 gene and
たのに対し(早期像:1.67
± 0.18,後期像:1.95
± 0.05)
carrying
the Gly2019Ser
in the
gene
and,
1family
patient
from another
family with
theLRRK2
Ile2020Thr
mu1他の
patient
from
another
family
withuptake,
the Ile2020Thr
mu6 had
例では
MIBG
取り込みが低下しており
(早期像
1.16
tation
normal
cardiac
MIBG
while
the:
retation
had
normal
cardiac
MIBG
uptake,
while
the
remaining
2 patients from
the third
family carrying the
± 0.02,後期像:1.16
± 0.02)
,各対照平均値より
3SD
maining
2
patients
from
the
third
family
carrying
the
Ile2020Thr mutation had decreased cardiac MIBG
Parkin
以上低かった(Table
。詳述すると,ホモ接合の
Ile2020Thr
mutation2)
had
decreased cardiac MIBG
uptake.
uptake.
変異を伴う患者
4 例中
3 例,DJ-1
変異を伴う患者
2 例中
Why genetic PD
displays
a heterogeneous
pattern
of
Why
genetic
PD
displays
a
heterogeneous
pattern
of
cardiac
MIBG変異を伴う兄弟
uptake is still unknown.
On the basis
of
1 例,PINK1
2 例中 1 例,LRRK2
遺伝子
cardiac
MIBG
uptake
is
still
unknown.
On
the
basis
of
the above-mentioned studies showing a link between
に Gly2019Ser
変異を伴う患者
6 例中 3 例では,MIBG
取
the
above-mentioned
studies
showing
a
link
between
Lewy pathology, cardiac sympathetic degeneration, and
Lewy
pathology,
cardiac
sympathetic
degeneration, that
and
5,10,17,18
り込みが正常であったのに対し,これら以外の家族性
PD
low
MIBG
uptake,
it can be hypothesized
5,10,17,18 it can be hypothesized that
low
MIBG
uptake,
genetic
PD without Lewy
bodies
show a変異
normal
Parkin
患者 6 例(ホモ接合の
変異might
1 例,DJ-1
1 例,
genetic PD
without
Lewy
bodies
mightwith
show
a normal
cardiac
MIBG
uptake,
while
patients
genetic
PD
PINK1
変異
1 例,LRRK2
変異
3 例)では心筋のトレーサ
cardiac
MIBG
uptake,
while
patients
with genetic
PD
and
Lewy
body
pathology
might
have decreased
MIBG
and
Lewy
body
pathology
might
have
decreased
MIBG
uptake.
Recent studies in PD patients with
mutation
in
取り込みが著しく低下していた(Table
2)
。MIBG
取り込
uptake. or
Recent
studies
inshowed
PD patients
with mutation
in
Parkin
LRRK2
genes
a
pleomorphic
range
of
みは,Parkin 遺伝子にホモ接合変異を伴う PD の同胞間
Parkin
or LRRK2 genes showed a pleomorphic range of
(Figure 1)
,およびホモ接合 PINK1 変異を伴う PD の 2 例
の兄弟間でも異なっていた(Figure 2)
。
Movement Disorders, Vol. 23, No. 1, 2008
Disorders, Vol. 23, No.比の低
1, 2008
家族性 PD 患者を H/MMovement
比で分類すると,H/M
5
123
26
A. QUATTRONE
家族性パーキンソン病患者の心筋における
I-MIBG の取り込み
26
ET AL.
A. QUATTRONE ET AL.
カラー原図をモノクロで掲載しております。
FIG. 2. Myocardial 123Metaiodobenzylguanidine (MIBG) planar anterior view and regional radiolabeled MIBG uptake
4 hr p.i., in 2 brothers with
homozygous
PINK1 123
mutations.
Planar anterior view
of theplanar
patient
PINK1-I
(a)and
showed
severe
decrease MIBG
of cardiac
MIBG
FIG.
2. Myocardial
Metaiodobenzylguanidine
(MIBG)
anterior
view
regional
radiolabeled
uptake
4 hr uptake,
p.i., in 2whereas
brothersMIBG
with
uptake was normal
the PINK1-II
patient
(b). view
Regional
MIBG
uptake
in the(a)
PINK1-II
showedofhigh
MIBG
activity
in allwhereas
the regions
of
homozygous
PINK1inmutations.
Planar
anterior
of the
patient
PINK1-I
showed patient
severe (c)
decrease
cardiac
MIBG
uptake,
MIBG
the heart.
uptake
was normal in the PINK1-II patient (b). Regional MIBG uptake in the PINK1-II patient (c) showed high MIBG activity in all the regions of
the heart.
pathologies with or without Lewy bodies. Indeed, Parpathologies
withParkinsonisms
or without Lewy
bodies.
Parkin-associated
usually
lackIndeed,
Lewy body
20-22
病期間:平均
20.50
±
12.44,p
=
0.332,HY
分類:中央
kin-associated
Parkinsonisms
usually
lack
Lewy
body
pathology,
but patients with mutations in the Parkin
pathology,
but
patients
mutations
in therecently
Parkin
gene
with 20-22
Lewy
bodies
in with
the brain
have been
値
3.0,範囲
2~
4,p
= 0.257,発症年齢:平均
40.83
±
23,24
gene
with
Lewy
bodies
in
the
brain
have
been
recently
reported.
Similarly, it has been reported that PD
12.25,p
=
0.850,L—ドパ用量:平均
620.8
± 112.3,p
=
23,24
reported.
Similarly,
it has
been
reported
thatLewy
PD
patients with
the
Gly2019Ser
may
or may
not have
patients
with the 比
Gly2019Ser
may
or may
not年have
0.304)と,H/M
が
常 な25-28
患 者(8
例,
齢:Lewy
平
均
while
individuals
with
body pathology
in
the正brain,
25-28 while individuals with
body
pathology
in
the
brain,
familial
PD carrying other LRRK2
mutations,
as
56.12
± 11.76,罹病期間:平均
14.00 ±
11.49,HYsuch
分類:
familial
PD Tyr1699Cys,
carrying otherdoLRRK2
mutations,
such as
Ile2020Thr,
not have
Lewy bodies
in
中央値
2.5,範囲
2 ~together,
4,発症年齢:42.12
± 12.41,L—ド
29,30
Ile2020Thr,
Tyr1699Cys,
do not
Lewy
bodiesthat
in
the brain.
Taken
thesehave
findings
suggest
29,30 Taken together, these findings suggest that
the
brain.PD
パ用量:平均
525.0 ±carrying
194.6)との間に,いずれの変数に
genetic
patients
the same gene mutation or
genetic
PD
patients in
carrying
thegene
same gene mutation or
different
mutations
the
same
おいても有意差は認められなかった。may have pleomordifferent
mutations
in
the
same
gene
may have
phic neuropathology (positive or negative
Lewypleomorbodies),
phic
neuropathology
(positive
or
negative
Lewy
which in turn might cause heterogeneous cardiacbodies),
MIBG
which
uptake.in turn might cause heterogeneous cardiac MIBG
考 察
uptake.
It is noteworthy that a heterogeneous MIBG uptake
It is
noteworthy
a heterogeneous
MIBG uptake
was
observed
in ourthat
siblings
with homozygous
Parkin
本研究では,様々な遺伝子変異を伴う家族性
患者
was
observed
in
our
siblings
with
homozygous
Parkin
mutations (1 of them had normal cardiac MIBGPD
uptake)
mutations
(1
of
them
had
normal
cardiac
MIBG
uptake)
and in
2 brothers
with homozygous
PINK1 mutations
では
14 the
例中
8 例で MIBG
取り込みは保たれていたのに
and in the 2 brothers with homozygous PINK1 mutations
い患者(6 例,年齢:平均 61.33 ± 13.72,p = 0.459,罹
対し,弧発性 PD 患者では全例で心筋 MIBG 取り込みが
著しく低下していた。すなわち,Parkin 変異を伴うパー
Movement Disorders, Vol. 23, No. 1, 2008
DJ-1 変異を伴う患者 1 例,
キンソン症候群患者
4 例中
例,
Movement Disorders, Vol. 23,
No. 1, 32008
6
(1 subject had normal MIBG while his brother showed
PINK1 変異を伴う兄弟の患者 2 例中 1 例,LRRK2 遺伝子
(1
subject decreased
had normalcardiac
MIBGMIBG
while his
brother
showed
markedly
uptake),
suggesting
に
Gly2019Ser
変
異
を
伴
う
患
者
6
例
中
3
例
に
おい
て,
markedly
decreased
cardiac
MIBG
uptake),
suggesting
that the same gene mutation might be associated
with
that
the
same
gene
mutation
might
be
associated
with
pleomorphic
Lewy pathology also in individuals from
MIBG 取り込みは正常であった。
pleomorphic
LewyPathologic
pathologyevidence
also in individuals
the same family.
supports thisfrom
hyMIBG
はノルエピネフリンの類似体であり,その取り
19
the
same
family.
Pathologic
evidence
supports
hypatient
pothesis. Indeed, some authors reported that 1this
14
19 reported that 1 patient
pothesis.
Indeed, mutation
some authors
。
込みと貯蔵の機序は内因性神経伝達物質と類似する
with
Ile2020Thr
in the
LRRK2 gene from the
with
Ile2020Thr
mutation
in
the
LRRK2
gene
from
the
Sagamihara
family had Lewy body pathology, while
MIBG 取り込みは,交感神経系のシナプス前部が完全な
Sagamihara
familymembers
had Lewy
body
pathology,
while
most of the other
of his
family
were negative
状態にあることを示し,本トレーサの心筋取り込みが低
most
of
the
other
members
of
his
family
were
negative
for Lewy bodies.
for
Lewyare
bodies.
下している場合は心臓交感神経系の機能低下ないし脱神
There
some limitations to this study. We lack pathoThere
are
some
to this
study.our
Wepatients
lack pathologic
data,
and
do not know
whether
with
15limitations
経が示唆されるwe
。
logic
data,
and
we
do
not
know
whether
our
patients
with
genetic PD and impaired MIBG cardiac uptake have Lewy
大部分の
PDimpaired
MIBG
取り込みが著明に低下
genetic
PD and
MIBG
cardiac
uptake
have
Lewy
body
pathology
in患者で心筋
the brain
and
sympathetic
nerve
endings.
1-4 nerve endings.
body
pathology
in
the
brain
and
sympathetic
However,
at present, very few pathologic 。MIBG
data have取り込
been
していることを示すエビデンスがある
However,
present, very
few fibers
pathologic
data PD,
haveand
been
reported onatsympathetic
nerve
in genetic
no
み低下は,PD の早期と晩期において,また自律神経障害
reported
sympathetic
nerve
fibers infindings
genetic in
PD,
andand
no
evidenceon
exists
concerning
pathologic
brain
がなくても認められており,MIBG
心筋シンチグラフィー
evidence
exists
concerning
findings
in brain and
sympathetic
nerve
endingspathologic
in subjects
with homozygous
sympathetic
nerve
endings
in
subjects
with
homozygous
PINK1
or DJ-1 mutations.
が PD の早期診断,ならびに無症状の自律神経障害の早
PINK1 or DJ-1 mutations.
6,7
期発見に役立つ可能性が示唆されている 。
多数の弧発性 PD 患者を対象とした最近のある研究 4
では,病期が進行した患者ほど心筋 MIBG H/M 比が低い
A. Quattrone et al.
ことが明らかにされ,心筋 MIBG 取り込みが PD の重症
異を伴う別の家系の 1 例は心筋 MIBG 取り込みが正常で
度と逆相関する可能性が示された。しかし,今回の知見
あったのに対し,Ile2020Thr 変異を伴う第 3 の家系の残
はこの観察結果とは異なり,HY 分類と MIBG H/M 比は
りの 2 例では心筋 MIBG 取り込みが低下していた。
弧発性 PD 群よりも家族性 PD 群で高く,また H/M 比が
家族性 PD 患者の心筋 MIBG 取り込みパターンが一様
正常な家族性 PD 患者と MIBG 取り込みが低下している
でない理由は不明である。ただし,上述の研究で示され
家族性 PD 患者との間に臨床的な差はみられなかった。
たようなレビー小体の病理変化,心臓交感神経変性およ
この結果から,家族性 PD 患者では疾患重症度とは独立
び MIBG 取り込み低下が関連するという知見 5,10,17,18 に基
して節後交感神経の脱神経が生じる可能性が示唆され
づくと,レビー小体のない家族性 PD では心筋 MIBG 取
る。
り込みが正常であり,レビー小体の病理変化を伴う家族
これまでの研究により,レビー小体に病理変化がなく
性 PD 患者では MIBG 取り込みが低下しているという仮
Parkin 変異を伴うパーキンソン症候群の患者数例では心
説を立てることもできる。Parkin または LRRK2 遺伝子に
筋 MIBG 取り込みが保たれていることが示されたが
,
9,10
変異を伴う PD 患者に関する最近のいくつかの研究では,
本研究の知見はこれらの研究成果を進展させるものであ
レビー小体を伴うあるいは伴わない多彩な病理所見が明
る。剖検を行った研究では,Parkin 遺伝子にホモ接合変
らかになった。すなわち,Parkin 変異を伴うパーキンソ
異を伴う患者の心外膜におけるチロシン水酸化酵素
ン症候群ではレビー小体の病理変化は通常認められない
(tyrosine hydroxylase; TH)免疫反応性神経線維はよく保
が 20-22,最近になって脳にレビー小体をもつ Parkin 遺伝
存されていたのに対し 9,レビー小体が病理学的に確認さ
子変異患者が報告された 23,24。同様に,Gly2019Ser 変異
れた弧発性 PD 被験者では,これらの神経線維が著明に
を伴う PD 患者では脳にレビー小体の病理変化が認めら
減少ないし消失していた
。この所見から,Parkin 変異
れる場合と認められない場合があり 25-28,Ile2020Thr や
を伴うパーキンソン症候群患者で完全な状態の心臓交感
Tyr1699Cys といった他の LRRK2 変異を伴う家族性 PD
神経線維がみられるのはレビー小体の病理変化の欠如に
患者では,脳にレビー小体が認められないことが報告さ
よる可能性があり,これによって正常な心筋 MIBG 取り
れている 29,30。以上の知見を総合すると,同一遺伝子変
込みが説明できるかもしれない。上記の観察結果に一致
異あるいは同一遺伝子に異なる変異を伴う家族性 PD 患
し,病理学的なエビデンスにより,PD 患者の交感神経節
者は,多彩な神経病理学的所見(レビー小体陽性あるい
内
は陰性)を示す可能性があり,ひいては,これが心筋
17
9,16
および心臓の節後交感神経内
18
にレビー小体が存在
することが証明されており,レビー小体の病理変化その
MIBG 取り込みを多様化させていると考えられる。
ものが心臓交感神経における高度の脱神経ならびに
今回の重要な知見として,ホモ接合 Parkin 変異を伴う
MIBG 取り込み低下を引き起こす可能性が示唆されてい
同胞例(うち 1 例は心筋 MIBG 取り込み正常)ならびに
る。
ホモ接合 PINK1 変異を伴う兄弟 2 例(1 例は MIBG 取り
本研究は,
家族性 PD 患者の心筋 MIBG 取り込みパター
込み正常,その兄は取り込みが著明に低下)で,MIBG
ンが一様ではないことも示している。すなわち,異なる
取り込みに不一致が認められた。このことから,同一遺
遺伝子に変異を伴う PD 患者間,同一遺伝子に異なる変
伝子変異を伴う同一家系の複数の個体においても,多彩
異を伴う非血縁患者間(DJ-1 変異患者は 2 例中 1 例で,
なレビー小体の病理変化がみられる可能性が示唆され
Parkin 変異患者は 4 例中 1 例で心筋 MIBG 取り込みが低
る。病理学的なエビデンスでもこの仮説は支持されてい
下していた)
,さらには同一遺伝子変異を伴う非血縁患者
る。ある論文 19 では,LRRK2 遺伝子に Ile2020Thr 変異を
間(LRRK2 遺伝子に Gly2019Ser 変異を伴う患者 6 例中 3
伴う Sagamihara 家系の患者 1 例でレビー小体の病理変化
例で心筋 MIBG 取り込みが著明に低下していたのに対し,
が認められたが,この男性患者以外の家系構成員の大部
他の 3 例では正常に保たれていた)でも,MIBG 取り込
分にレビー小体は認められなかったと報告している。
みにはばらつきが認められた。同様の結果は,最近,
本研究にはいくつかの限界がある。本研究では病理学
LRRK2 変異を伴う 3 つの小家系の日本人患者 5 例でも報
的データを入手していないため,心筋 MIBG 取り込みが
告されている 。この日本人患者のうち,LRRK2 遺伝子
低下した家族性 PD 患者において,レビー小体の病理変
に Gly2019Ser 変異を伴う同一家系の 2 例と Ile2020Thr 変
化が脳や交感神経終末にみられるかどうかは不明である。
19
7
636.
10. Orimo S, Amino T, Yokochi M, et al. Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in
PARK2. Mov Disord 2005;20:1350-1353.
家族性パーキンソン病患者の心筋における 123I-MIBG の取り込み
11. Singleton A, Gwinn-Hardy K, Sharabi Y, et al. Association between cardiac denervation and parkinsonism caused by
-synuclein gene triplication. Brain 2004;1227:768-772.
12. Mathias CJ, Bannister R. Clinical autonomic testing. In: Mathias
現時点では,家族性 PD 患者の交感神経線維に関する病
CJ, Bannister R, editors. Autonomic failure. A textbook of clinical
理 学的データの報告はきわめて少なく,ホモ接合の
disorders of the autonomic nervous system. Oxford: Oxford University Press; 1999. p 171-178.
123
PINK1 あるいは DJ-1
変異を伴う患者の脳と交感神経終
MYOCARDIAL
METAIODOBENZYLGUANIDINE
UPTAKE
IN GENETIC
PDmutations and parkin27
13. Annesi G,
Savettieri, Pugliese
P, et al. DJ-1
sonism-dementia-amyotrophic lateral sclerosis complex. Ann Neu末の病理所見についてはエビデンスが得られていない。
rol 2005;58:803-807.
14. Wieland DM, Wu JL, Brown LE, et al. Radiolabeled adrenergic
In conclusion, differing
from idiopathic
PD, patients
結論として,家族性
PD 患者の心筋
MIBG 取り込みは,
neuron-blocking agents: adrenomedullary imaging with [123I]Me123
with genetic PDMYOCARDIAL
can show normal
or decreased cardiac
METAIODOBENZYLGUANIDINE
UPTAKE IN GENETIC PD
27
taiodobenzylguanidine. J Nucl Med 1980;21:349-353.
弧発性 PD 患者とは異なり正常な場合と低下している場
MIBG uptake, suggesting that cardiac MIBG scintigra15. Hakusui S, Yasuda T, Yanagi T, et al. A radiological analysis of
合の両方がある。したがって,心筋
MIBG
heart sympathetic functions with meta-[123I]Metaiodobenzylguaniphy is not useful to distinguish patients
withシンチグラ
genetic PD
14. Wieland
Wu JL,patients
Brown with
LE, et
al. Radiolabeled
In conclusion, differing from idiopathic PD, patients
dine in DM,
neurological
autonomic
failure. J adrenergic
Auton Nerv
from those withPD
idiopathic PD. Whether
this heterogeneuron-blocking
agents: adrenomedullary imaging with [123I]Meフィーは家族性
患者の鑑別に有用
Syst 1994;49:81-84.
with
genetic PD can患者と弧発性
show normal PD
or decreased
cardiac
taiodobenzylguanidine. J Nucl Med 1980;21:349-353.
neous pattern of cardiac MIBG uptake is related to the
16. Amino T, Orimo S, Itoh Y, et al. Profound cardiac sympathetic
MIBG
uptake, suggesting that
cardiac
MIBG scintigraでないと考えられる。心筋
MIBG
取り込みパターンにお
15. Hakusui
S, Yasuda
T, et al.
A radiological
analysis
of
presence or the absence of Lewy body pathology in
denervation
occursT,inYanagi
Parkinson’s
disease.
Brain Pathol
2005;15:
heart
sympathetic functions with meta-[123I]Metaiodobenzylguaniphy
is
not
useful
to
distinguish
patients
with
genetic
PD
29-34.
けるこのような多様性が,心臓交感神経におけるレビー
cardiac sympathetic nerves remains to be determined.
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Syst 1994;49:81-84.
小体の病理変化の有無に関連しているかどうかは不明で
visceral autonomic nervous system in Parkinson’s disease. In:
neous
pattern of cardiac
MIBG
uptake
is
related
to
the
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8
Movement Disorders, Vol. 23, No. 1, 2008
26. Gilks
mutati
416.
27. Ross O
Ann N
28. Rajpu
G2019
29. Zimpr
autoso
Neuro
30. Giorda
Parkin
tion. M
パーキンソン病における衝動制御障害の長期追跡
調査
Long-Term Follow-Up of Impulse Control Disorders in Parkinson’s Disease
*
Eugenia Mamikonyan, MS, Andrew D. Siderowf, MD, MSCE, John E. Duda, MD, Marc N. Potenza, MD, PhD, Stacy
Horn, DO, Matthew B. Stern, MD, and Daniel Weintraub, MD
*
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania
最近,
複数の研究により,
ドパミンアゴニスト(dopamine
査時に投与されている DA のレボドパ(L—ドパ)換算 1
agonist; DA)の使用がパーキンソン病(Parkinson’
s
日用量(levodopa equivalent daily dosage; LEDD)
disease; PD)における衝動制御障害(impulse control
,L—ドパの 1
は有意に低く(Z =- 3.1,p = 0.002)
disorder; ICD)の発現と関連することが報告されてい
,総
日 用 量 は 高 か っ た が(Z = - 1.9,p = 0.05)
る。こうした ICD 患者の至適管理法や長期アウトカム
,
LEDD はほぼ同じであり(Z =- 0.47,p = 0.64)
については,ほとんど知られていない。本研究の目的は,
Unified Parkinson’
s Disease Rating Scale PartⅠ
(運
Ⅰ
Ⅰ
DA 投与開始後に ICD を発現した PD 患者の臨床的介入
動)のスコアにも差を認めなかった(Z =- 1.3,p =
法と長期アウトカムを報告することである。ベースライ
0.19)
。ICD 管理の一環として患者 12 例(80.0%)で
ン時から平均 29.2 ヵ月後に電話による追跡調査面接を
は DA が投与中止または大幅に減量されていたが,全例
行った。強迫的な買い物・賭博・性行動に関する修正
で自己評価による ICD 症状は完全または部分寛解し,
Minnesota Impulse Disorder Interview(MIDI)に加え,
うち 10 例(83.3%)ではすでに ICD の診断基準を満
ICD 症状の変化に関する被験者の自己評価も調査した。
たさなくなっていた。DA 投与中に ICD を発現した PD
ベースライン時および追跡調査時のドパミン補充療法の
患者は,DA の投与中止または大幅な減量により(代わ
実施状況を記録し,診療録をレビューして確認した。被
,運動症状の増悪を伴
りに L—ドパを増量したとしても)
験者 18 例のうち 15 例(83.3%)が電話による追跡調
うことなく,ICD 症状は寛解または有意に抑制される。
査面接に参加した。ベースライン時に比べると,追跡調
Movement Disorders Vol. 23, No. 1, 2008, pp. 75-80
Key Word ドパミンアゴニスト,賭博,衝動制御障害,パーキンソン病
パーキンソン病(Parkinson ’s disease; PD)患者では,
強迫的な賭博 ,性行動
ニスト(dopamine agonist; DA)の使用を指摘しているが,
,買い物 ,摂食 など,数多
一方ではレボドパ(L—ドパ)使用との関連も報告されて
くの衝動制御障害(impulse control disorder; ICD)が高い
いる 12。ICD 発現に関するその他の危険因子として,低
頻度で報告されている。PD 患者における ICD の推定発
年齢での PD 発症 11,PD 罹患以前の ICD 3 または薬物乱
現頻度は一般集団より高いのが普通であり 7,全体では常
用 11 の既往歴も考えられる。
1
2-4
3,5
6
に患者の約 5%に ICD がみられ 3,8,PD 経過中のある時点
ICD を有する PD 患者の至適管理法や長期アウトカム
については,ほとんど知られていない。事例的には,DA
では 5 ~ 10%に達することがある 。
2,3
は,PD
の投与中止,使用中の DA の減量,あるいは別の DA へ
における ICD 発現の主要な危険因子としてドパミンアゴ
の変更など,DA 療法の変更に伴って ICD 症状が改善な
いくつかの症例報告
4,5,8-10
および前向き研究
3,11
9
パーキンソン病における衝動制御障害
いし消失した例が報告されている 4,6,9,10。症例報告では,
PD における ICD 治療として,非定型抗精神病薬
抗うつ薬
,
4,13,14
方法
電話による追跡調査面接を行うため,
著者の 1 人(EM)
9,12
が患者に連絡を取った。初回スクリーニング(活動性
の有益性を示唆している。ただし,これらの治療法はド
ICD 患者の場合)または自己申告に基づく ICD 症状の極
パミン補充療法の変更と同時に実施されることが多く,
期(非活動性 ICD 患者の場合)
(Time 1)から,追跡調
個別の効果は明らかでない。また,日常診療の一環とし
査面接(Time 2)までの平均(SD)期間は 29.2(16.5)ヵ
て視床下核(subthalamic nucleus; STN)深部脳刺激(deep-
月であった。
,気分安定薬
4,12
,種々の心理社会的介入
4,9
brain stimulation; DBS)を受けた PD 患者(598 例)のア
追跡調査面接では,半定型的な臨床面接と,強迫的な
ウトカムに関する症例研究では,DBS 前に病的賭博がみ
買い物・賭博・性行動に関する修正 Minnesota Impulse
られたすべての患者(7 例)で,術後は症状が消失した
Disorder Interview(MIDI)16 を実施した。これと同じ方
ことが報告されている 15。この論文の著者らは,DBS の
法は,本 ICD コホートに関する最初の報告 3 でも用いた。
生理学的作用が,
同時に行われた DA 全体の減量と相まっ
被験者には,各自の ICD が「完全寛解」
(症状なし)
,
「部
て ICD 症状を改善したという仮説を立てている。ただし,
分寛解」
(依然として症状はあるが,重大な機能障害はな
彼らの研究結果は,L—ドパ療法と DA 療法での変更を区
い)
,
「完全に症状が残存」
(時間が経っても症状に変化が
別しておらず,STN DBS を受けた PD 患者の中の少数の
ない)のいずれの状態にあるか,自己評価してもらった。
ICD 患者を対象としている。したがって,この知見は PD
面接の一部として,各被験者から ICD 症状の初回発現
患者全体に一般化できない可能性がある。
日および消失日,ICD 症状に対する介入(例えば,抗 PD
我々は,以前,PD の経過中に ICD を発現した 273 例
薬の増量ないし減量,向精神薬の使用,あるいは心理社
のサンプルのうち,症状発現時に DA を使用していた 18
会的治療の実施)
,さらに PD および精神疾患に対する過
例について報告した 。本論文では,これらの患者の ICD
去と現在の薬物療法について,情報を収集した。これら
に関する長期アウトカムを報告する。ドパミン補充療法
の情報はすべて診療録のレビューで確認し,さらに別の
または PD 管理法の経時的な変更,および ICD への臨床
著者(DW)が再検討した。Time 1 および Time 2(± 6 ヵ
的介入に関する情報を収集した。我々は DA の投与中止
月)における Unified Parkinson’ s Disease Rating Scale
または減量が ICD の改善や消失に関連しているとの仮説
(UPDRS)17 PartⅠ
Ⅰ
Ⅰ(運動)のスコアは,
診療録をレビュー
3
を立て,検証を行った。
して入手した。本研究の目的に鑑み,DA 用量の 30%を
超える減量を大幅な減量と事前に定義した。
対象および方法
対象
統計解析
L—ドパの 1 日用量,
DA の L—ドパ換算 1 日用量(L-dopa
PD 患者のうつ病発現頻度および関連因子に関する研
equivalent daily dosage; LEDD)
,総 LEDD(L—ドパ+ DA
究で作成されたデータベースを用い,PD 経過中に活動
の LEDD)
,UPDRS PartⅠ
Ⅰ
Ⅰ(運動)のスコアの Time 1 お
性 ICD がみられた PD 患者を特定した(方法はすでに報
よび Time 2 での各変化は,関連する 2 群間の差の検定に
告済み )
。初回の評価では,18 例の患者で PD 経過中に
用いられる Wilcoxon 符号付順位検定により検討した。
ICD が認められた(活動性 ICD は 11 例,寛解期 ICD は
LEDD は従来の報告 18,19 と同様の次式で計算した:L—ド
7 例)
。このうち 15 例(83.3%)が電話による追跡調査面
パ 100 mg =放出制御型 L—ドパ 130 mg = L—ドパ 70 mg
接に参加した。追跡調査に参加した患者の自己申告およ
+ COMT 阻害剤=ペルゴリド 1 mg =プラミペキソール
び診療録のレビューで ICD 症状の極期と判定された時点
1 mg =ロピニロール 5 mg。p ≦ 0.05 を有意とした。
3
での臨床的・人口学的特徴は次の通りであった。すなわち,
性別は 73.3%が男性,
婚姻区分は 86.7%が既婚,
平均(SD)
年齢は 60.9(11.1)歳,平均(SD)教育期間は 14.8(3.0)
年,平均(SD)PD 罹病期間は 9.4(4.6)年であった。
結 果
Time 1
Time 1 では被験者 15 例全例が DA の投与を受けてい
10
Compulsive
gambling
Compulsive
gambling
Compulsive
gambling
Compulsive
buying
Compulsive
buying
Compulsive
gambling,
buying,
sexuality
Compulsive
gambling
Compulsive
sexuality
Compulsive
gambling
Compulsive
gambling,
sexuality
Compulsive
sexuality
Compulsive
sexuality
Compulsive
gambling
Compulsive
sexuality
2
4
7
9
10
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
DA
use
Pramipexole
(6)
Ropinirole
(12)
Ropinirole
(9)
Pramipexole
(2.75)
Pramipexole
(2.25)
Ropinirole
(21)
Pramipexole
(4.5)
Ropinirole
(4.5)
Ropinirole
(15)
Pergolide
(8)
Ropinirole
(18)
Ropinirole
(12)
Pramipexole
(3)
Pramipexole
(4)
Pergolide
(5)
DA and
dose (mg/
day)
0
0
280
400
0
0
425
390
1,320
0
210
800
800
210
500
Levodopa
dosage
(mg/day)
*N 14, UPDRS scores unavailable for 1 patient.
15
14
13
12
11
8
6
5
3
Compulsive
sexuality
ICD type
1
Subjects
no.
Time 1
7
21
–
36
32
10
29
30
26
24
20
29
24
13
16
UPDRS*
17 mo
17 mo
58 mo
18 mo
18 mo
71 mo
20 mo
23 mo
24 mo
29 mo
35 mo
16 mo
22 mo
46 mo
25 mo
Time 2 –
Time 1
Yes
No
Yes
Yes
Yes
No
Yes
No
No
Yes
No
Yes
Yes
No
No
DA use
Pramipexole
(1)
Ropinirole
(6)
Not
applicable
Pramipexole
(1.875)
Not
applicable
Ropinirole
(21)
Pramipexole
(4.5)
Not
applicable
Not
applicable
Not
applicable
Pramipexole
(1.25)
Pergolide (8)
Not
applicable
Pramipexole
(1.5)
Not
applicable
DA and dose
(mg/day)
Time 2
0
325
330
700
300
390
390
520
1,310
0
140
1,010
700
720
400
Levodopa
dosage
(mg)
11
23
–
38
42
10
12
28
35
32
22
19
31
17
24
UPDRS*
TABLE 1. Changes in clinical management and ICD status over time
Discontinued
ropinirole
Decreased pramipexole
Decreased ropinirole
Decreased pramipexole
Discontinued
ropinirole; increased
antidepressant
dosage
Underwent DBS
surgery; decreased
amantadine
Discontinued
pramipexole
None
Discontinued
ropinirole
Decreased DA dosage
(switched from
ropinirole to
pramipexole)
Discontinued
ropinirole
Discontinued
pergolide; attended
sex addiction
support group
Discontinued
pramipexole
Decreased pramipexole
dosage; Switched
antidepressant
None
Intervention for ICD
Full
remission
Compulsive
gambling
Full
remission
Outcome:
MIDI
Partial
remission
Full
remission
Full
remission
Full
remission
Full
remission
Partial
remission
Full
remission
Full
remission
Full
remission
Compulsive
sexuality
Full
remission
Full
remission
Full
remission
Full
remission
Compulsive
gambling
Full
remission
Full
remission
Full
remission
Fully
Compulsive
symptomatic gambling
Full
Full
remission
remission
Full
Full
remission
remission
Full
remission
Partial
remission
Full
remission
Outcome:
self report
ICD status
IMPULSE CONTROL DISORDERS IN PARKINSONS DISEASE
Eugenia Mamikonyan
77
Movement Disorders, Vol. 23, No. 1, 2008
11
78
パーキンソン病における衝動制御障害
E. MAMIKONYAN ET AL.
TABLE 2. Changes in levodopa equivalent daily dosages (LEDDs) and UPDRS score over time
Time 1 (mean [SD])
Time 2 (mean [SD])
Average % change
Statistic
(Z score [P value])*
358.7 (179.4)
349.7 (381.3)
708.3 (482.9)
22.6(8.7)
170.2 (233.3)
482.3 (358.9)
652.5 (465.3)
24.6(10.2)
52.6
37.9
7.9
8.8
3.1 (0.002)
1.9 (0.05)
0.5 (0.64)
1.3(0.19)
Dopamine agonist LEDD
Levodopa daily dosage
Total LEDD
UPDRS motor scorea
*Wilcoxon Signed Ranks Test.
a
N 14, UPDRS scores unavailable for 1 patient.
(13%). Thirteen
(87%)
subjects had a single ICD, while
た(Table
1)
。各 DA
の使用割合は,プラミペキソールが
two subjects had two or more ICDs. Approximately half
40%,
47%,ペルゴリドが
13%であった。
(53%)ロピニロールが
of subjects were
compulsive gamblers,
40% excompulsive
behavior, and 20% had
13perienced
例(87%)では
1 つのsexual
ICD 症状だけがみられたが,2
compulsive buying. Mean (SD) daily dosages of PD
例では複数の ICD 症状を有していた。また,被験者の約
medications and UPDRS motor score were as follows:
半数(53%)は強迫的な賭博常習者,40%は強迫的な性
L-dopa 349.7 (381.3) mg, DA LEDD 358.7 (179.4)
mg, total LEDD 708.3 (482.9) mg, and UPDRS motor
行動経験者であり,20%で強迫的な買い物がみられた。
score 22.6 (8.7).
抗 PD 薬の平均(SD)1 日用量と UPDRS PartⅠ
Ⅰ
Ⅰ(運動)
Time 2
のスコアは以下の通りであった:L—ドパ=
349.7(381.3)
At Time
2 approximately
half (53%) LEDD
of the=
sample
mg,DA
の LEDD
= 358.7(179.4)mg,総
708.3
remained on a DA. Of the subjects remaining on a DA,
(482.9)mg,
UPDRS
PartⅠ
Ⅰ
Ⅰ(運動)のスコア=
22.6(8.7)
。
63% were on
pramipexole,
25% on ropinirole,
and 13%
on pergolide. Mean (SD) daily dosages of PD medications and UPDRS motor score were as follows: L-dopa Time 2
482.3 (358.9) mg, DA LEDD 170.2 (233.3) mg, total
Time 2では,被験者の約半数(53%)で
DA 投与が継
LEDD
652.5 (465.3) mg, and UPDRS motor
score 24.6 (10.2). Over time
there was a63%がプラミペキソー
statistically significant
続されていた。DA
投与継続例の
increase in L-dopa dosage (Z 1.9, P 0.05) and a
ル使用で,25%がロピニロール,13%がペルゴリドであっ
statistically significant decrease in DA LEDD (Z た。抗
薬の平均
日用量と
Ⅰ
Ⅰ
Ⅰ
(運動)
3.1, PD
P
0.002),(SD)
with 1no
change UPDRS
in total Part
LEDD
(Z 0.5, P 0.64). There was no :
change
in UPDRS
motor
のスコアは以下のとおりであった
L—ドパ=
482.3(358.9)
score over time (Z 1.3, P 0.19) (Table 2).
mg,DA の LEDD = 170.2(233.3)mg,総 LEDD = 652.5
As part of clinical management for the ICD, 12 (80%)
(465.3)mg,
UPDRS
PartⅠ
Ⅰ
Ⅰ
(運動)のスコア=
。
patients either
discontinued
DA treatment24.6(10.2)
or significantly decreased their DA dosage. Of these Zpatients,
all
経時的に,L—ドパの統計学的に有意な増量(
= –1.9,p
reported experiencing full or partial remission of their
= 0.05)と,DA の LEDD の統計学的に有意な減少(Z
ICD symptoms, and 10 (83%) no longer met criteria for
=
0.002)が認められたが,総
LEDD
に変化は
an–3.1,p
active =
ICD.
Of the 7 (47%) patients who
discontinued
DA treatment,
all reported
full。UPDRS
remissionPart
of ICD
sympなかった(Z
= –0.5,p
= 0.64)
Ⅲ(運動)
toms over time and none still met diagnostic criteria for
のスコアにも経時的な変化はみられなかった(Z
= 1.3,
an active ICD.
p =Only
3(Table
(20%) 2)
patients
remained on the exact same DA
0.19)
。
and
dosage
over
time.
One
was in full12remission
postICD の臨床管理の一環として,患者
例(80%)で
DBS surgery and other medication adjustments, one was
DA
in の投与中止または大幅な減量が行われた。これら全
partial remission, and one remained fully
symptomatic.
例で
ICD 症状が完全または部分寛解したことが報告され,
Four patients who experienced full or partial remission
そのうち 10 例(83%)はすでに活動性 ICD の診断基準
reported clinical interventions for their ICD symptoms in
を満たしていなかった。DA
を投与中止された
7例
(47%)
addition to (N 3) or instead
of (N 1) changes
in DA
treatment. As a supplemental
treatment, one subject atは時間の経過とともに
ICD 症状が完全寛解し,活動性
ICD の診断基準を満たす者はいなかった。
DISCUSSION
例)
,ICD 症状への臨床的介入が行われた。補助療法と
To 1our
knowledge this is
the first case series examinして,
例は性的耽溺(sex
addiction)に関する支援グルー
ing in the context of routine care the long-term clinical
プの活動に参加し,2 例では抗うつ薬への変更もしくは
outcomes of PD patients with ICDs. We found that on
使用中の抗うつ薬が増量された。残りの患者
1 例は
DBS
average
patients had a significant change in their
specific
dopamine
replacement
therapies once their 後はアマン
ICD was
後も同じ DA
を同一用量で継続したが,DBS
identified, and that all patients who discontinued or sigタジンが投与中止された。
nificantly
decreased DA treatment experienced full remission or a clinically significant reduction in ICD
symptomatology. This was consistent with our hypothe考 察in exposure to DA therapy would be
sis that decreases
associated with improvement in ICD symptoms.
There are several limitations to this study.
we
今回の研究は,我々が知る限り,ICD
を伴うFirst,
PD 患者
were unable to contact all eligible subjects, although over
の長期臨床アウトカムを日常診療との関連において検討
80% of the original ICD sample did participate in the
した最初の症例集積研究である。本研究の症例では,
follow-up interview. Second, the sample size was relatively
small, only identified ICD patients on a DA, and
ICD と診断された後は患者個々のドパミン補充療法は大
involved patients at two movement disorders centers
幅に変更されており,また DA を投与中止ないし大幅に
with a research focus on the psychiatric complications of
減量したすべての患者で,ICD
PD,
limiting the generalizability症状は完全寛解ないし臨
of the findings. Third,
the
data were obtained primarily via telephone
interview.
床的に有意に軽快した。この結果は,DA
への曝露を低
In-person interviews may have yielded more accurate
減すると ICD 症状が改善されるという我々の仮説と一致
and complete information. Finally, this study was not
した。
controlled, limiting conclusions that could be drawn. For
example,
it is possible that the overall decrease
in DA
本研究にはいくつかの限界がある。第
1 に,当初の
exposure was unrelated to improvement in ICD sympICD 被験者の
80%超が実際に追跡調査面接に参加したと
toms,
as the natural
histories of ICDs in PD and non-PD
individuals
are not well understood.
はいえ,適格者全員に連絡を取ることはできなかった。
results of this study results provide further
第 The
2 に,サンプルサイズが比較的小さく,DA
投与 eviICD
dence of the association between DA treatment and ICD
患者のみをデータベースで特定し,PD
の精神科的合併
behaviors
in PD. Because of the long lag-time
reported in
many
cases between DA 2initiation
and development of
症を重点研究領域とする
つの運動障害関連施設の患者
ICD behaviors, it is not practical to conduct a randomを対象とした。この結果,今回の知見を一般化するには
ized trial to definitively determine the association be限界がある。第
3 に,データは主として電話面接によっ
tween
DA treatment
and ICDs. Additionally, given the
existing
evidence in support of the association between
て得られたものである。対面面接であれば,さらに正確
かつ完全な情報が得られた可能性がある。最後に,本研
同じ DA を同一用量でそのまま継続投与されたのは 3
究は対照群を置いていないため,得られた結論には限界
例(20%)のみであった。1 例は DBS 後および他の薬剤
がある。例えば,PD および非 PD 患者における ICD の自
Movement Disorders, Vol. 23, No. 1, 2008
12
tended
a sex addiction support group, and
two subjects
を適応された後,完全寛解した。別の
1 例は部分寛解に
changed antidepressant treatment or increased their an達したが,もう
1 例は完全に症状が残存した。
tidepressant
dosage.
The remaining patient continued on
the完全または部分寛解に達した患者
same DA and dosage post-DBS4 surgery,
but 治療
did
例では,DA
discontinue
amantadine
post-DBS
surgery.
の変更に加えて(3 例)
,
もしくは DA 治療の代替として(1
Eugenia Mamikonyan
然史はよく分かっていないため,DA 曝露の全般的な低
衝動は,DBS の神経刺激スイッチをオフにすることで消
減が ICD 症状の改善とは無関係であった可能性も考えら
失した。その後パラメータを変えて刺激を再開したとこ
れる。
ろ,ICD 症状が再発し,DA 投与を中止しない限り STN
本研究の結果は,PD における DA 投与と ICD との関
刺激の継続は不可能であった。このように,ICD 症状と
連性について更なるエビデンスを提供するものである。
PD 治療との関連性については,特に個々の患者特性を考
多くの症例で DA の投与開始と ICD に伴う問題行動発現
慮して,さらに研究を進める必要がある。
との間に長いタイムラグのあることが報告されているが,
また,DA 投与に伴い PD 患者で発現した ICD に対し,
DA 投与と ICD との関連性を確定するために無作為試験
他の治療法が有効であるかどうかを検討することも重要
を実施するのは現実的ではない。さらに,ICD と DA 投
である。本研究の対象患者 1 例は同じ DA を同じ用量で
与との関連性を支持するエビデンスの存在を考慮しても,
継続したにもかかわらず,ICD 症状が部分寛解したこと
ICD を伴う PD 患者を対象に無作為に DA の投与を中止
から,その他の因子が ICD 症状の経時的変化に寄与する
する試験を行うことは倫理的に妥当であるとは思えない。
可能性が示唆される。さらに PD 患者の多くは,DA を使
したがって,ICD に対する
DA 投与の影響について入手
の投与中止には
IMPULSE
CONTROL DISORDERS 用すると運動機能が改善するため,DA
IN PARKINSONS DISEASE
79
できる最良のエビデンスは,横断的研究ならびに臨床集
消極的である。したがって,非定型抗精神病薬や抗うつ
団の慎重な長期追跡調査で得られると考えられる。
ICDs and DA treatment, it does not seem ethical to
薬など,PDthat
患者の
治療への有用性が報告されてい
suggesting
otherICD
factors
may contribute to changes
in
ICD
symptoms
over
time.
In addition, many PD
る精神科用薬剤を用いて無作為投与試験を実施する必要
patients are reluctant to discontinue DA treatment be’ Anonymous(病的賭博患者の
がある。さらに,Gamblers
cause
of the motor benefits
associated with their use.
自助グループ)への参加など,心理社会的介入の役割に
Thus,
randomized treatment studies using psychiatric
medications
that have been reported to be helpful in the
ついても未だ研究がなされていない。このような他の治
treatment of ICDs in PD, such as atypical antipsychotics
療法の検証を待つ一方,DA
投与中の
ICD を管理するた
and
antidepressants, are needed.
Finally,
the role for
psychosocial
interventions, such as participation
in Gamめの比較的簡単かつ有効と思われる方法の
1 つとして,
blers’ Anonymous, has yet to be studied. However, while
DA 曝露の低減と L—ドパ増量を考慮すべきである。
waiting for other treatment strategies to be tested, one
謝 辞effective way to manage
relatively simple and apparently
ICDs
that occur during DA treatment is toInstitute
decrease
DA
本研究は米国立精神衛生研究所(National
of Mental
L
-dopa
exposure
and
consider
a
concomitant
increase
in
Health)の助成(No. 067894)を受けた。
treatment.
conduct
a randomizedを投与中止ないし減量すると
DA discontinuation study inICD
PD
今回の結果は,DA
patients with an ICD. Thus, the best available evidence
症状が抑制または消失するという,これまでの症例報告
regarding the impact of DA treatment on ICD behaviors
と矛盾しない。この結果は,STN
DBS studies
を施行した小規模
is likely to come from cross-sectional
and careful
long-term
follow-up
of
clinical
populations.
ICD 患者集団で認められたアウトカムとも類似している
Our results are consistent with previous case reporting
が,これらの患者ではいずれも
DBS
後,総
LEDD leads
の有
that discontinuation or reduction
in DA
treatment
15
to a reduction or resolution
of ICD symptoms.
意な減量に関連して
ICD 症状が消失した
。 They are
also similar to the outcomes of the small group of ICD
全体的にみると,患者の総 LEDD は 2 つの時点でほぼ
patients who underwent STN DBS surgery, all of whom
同じであったが,L—ドパおよび
投与間のバランスに
experienced resolution of ICDDA
symptomatology
postDBS
surgery
and
in
the
context
of
treatment
with
signifは全体として変化がみられた。すなわち,
Time 1 において,
icantly lower total LEDD.15
L—ドパの 1 日用量および DA の LEDD は本質的に同じで
We found that patients overall were being treated
あったが,Time
2 では,L—ドパ投与に比重が移っており,
with similar total
LEDDs at the two time periods, but
that
there
was
an
overall
shiftの
in4the
balance between
L—ドパの 1 日用量は DA LEDD
倍近くまで増加して
L-dopa and DA treatment. At Time 1, patients were on
いた。UPDRS PartⅠ
Ⅰ
Ⅰ(運動)のスコアに経時的な変化が
essentially the same daily L-dopa and DA LEDD dos認められなかったことから,DA
からshifted
L—ドパに投与バラ
age, but at Time 2 the balance
in favor of
L-dopa treatment, with the daily L-dopa dosage being
ンスを変更することで,全体として ICD 患者の運動症状
nearly four times as high as the DA LEDD dosage.
が適切に管理できることが示唆される。慢性的な高用量
The lack of change in UPDRS motor score over time
suggests that overall it is possible to adequately manL—ドパ投与は長期有害作用(例えばジスキネジアや
age motor
symptoms in ICD patients by shifting
the
20
motor
fluctuation)を引き起こす可能性もあるが
,今回
balance away from DA treatment to L-dopa treatment.
の結果は,DBS
施行患者で得られた知見と合わせ,PD
Though there may
be long-term adverse effects (e.g.,
dyskinesias
or motor fluctuations) from chronic,
high患者の
ICD 症状に対して有効と考えられる
2 つの管理法
er-dose L-dopa treatment,20 our results in conjunction
を示唆している。すなわち,L—ドパと DA の投与バラン
with those of patients undergoing surgery suggest that
スを変更して
DBSsympの施
two possibleL—ドパに比重を置くことと,STN
management strategies for ICD
toms
in
PD
are
shifting
the
L
-dopa:DA
balance
in
行であり,後者はドパミン作動性治療の全体的な抑制に
favor of L-dopa and STN DBS surgery, the latter
つながる。ただし,最近の症例報告では,両側 STN DBS
leading to a decrease in overall dopaminergic treat後に初めて認知機能低下を背景とする病的賭博が発現し
ment. However, it is important to note a recent case
report DA
of 投与の一例が報告されており,この知見に留
a patient on long-term DA treatment who
た長期
developed pathological
gambling only after post-bilat意する必要がある 21。ただし,この患者の賭博に対する
eral STN DBS and in the context of cognitive decline.21 The urge to gamble resolved after switching
off the neurostimulation. Upon restimulation with different parameters, ICD symptoms reoccurred, and
only with discontinuation of DA treatment was the
Acknowledgments: Supported by a grant from the National
Institute of Mental Health, No. 067894.
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Movement Disorders, Vol. 23, No. 1, 2008
14
ET A
diseas
comm
Herzo
subtha
Disord
Olano
for th
guidel
Smedi
Speelm
subtha
Neuro
A CLINICAL AND GENETIC STUDY OF MDS
contrast, in none of these patients a worsening of dysto-
31
None of the patients experienced a progression of the
nia was observed. The progression of myoclonus caused
motor symptoms
and no treatment had been given. The
ミオクローヌス・ジストニア症候群:11
家系の臨床像・疾患
a disability in performing daily activities and these pamovement disorder spontaneously improved in the two
経過・遺伝的特徴
tients were therefore given medication with different
older siblings of Family 3 after age 10.
drugs (clonazepam, valproic acid, levitiracetam), with no
Myoclonus–Dystonia
Syndrome: Clinical Presentation, Disease Electrophysiological
Course, and Genetic
Features in 11
Results
or only mild improvement. Noticeably, in Patient 10
Families
The data of EMG recordings are summarized in Table
benzodiazepines (diazepam and clonazepam) caused a
3. The EMG correlates of the myoclonic jerks demonsevere worsening of the myoclonic jerks. No patients
Nardo Nardocci, MD, Giovanna Zorzi, MD, Chiara Barzaghi, MSc, Federica Zibordi, MD, Claudia Ciano, MD, Daniele Ghezzi, MSc, and Barstrated bursts with a wide range of duration, from 60 to
received
any
treatment
for
dystonia.
bara Garavaglia, PhD
500 ms. The myoclonic jerks were evident at rest in 6
In
8
patients,
the
disease
course
was
nonprogressive:
*
Department of Child Neurology, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Via Celoria 11, Milano, Italy
patients, and in this circumstance the bursts occurred on
no modification of distribution or severity of myoclonus
a silent background (Fig. 2A). In all patients, voluntary
and dystonia was observed.
muscle activation produced or aggravated the myoclonic
In one case (Patient 3) a complete spontaneous remisjerks, which became repetitive with always an arrhythsion of myoclonus was observed by age 12.
ミオ クローヌス・ジ ストニア 症 候 群(myoclonusの
2 つの変異が認められた。大部分の患者ではミオク
mic
pattern. In 5 patients, there were also polymyoMutation-Negative Patients.
graphic features consistent with dystonia (cocontraction
dystonia syndrome; MDS)は,多様な臨床的・遺伝的
ローヌスとジストニアが組み合わさった症状がみられた
There were 4 patients from 2 unrelated families. In one
of agonist and antagonist muscles during voluntary
特徴を示す遺伝性の運動障害である。ε - サルコグリカ
が,非常に早期の発症,遠位ミオクローヌス,下肢障害
family (Family 9) the pedigree analysis indicated an
movements), and in these patients the myoclonic jerks
sarcoglycan;
)遺伝子変異は
MDS
ン(epsilon
といった非定型的と考えられる臨床所見もかなり高い割
autosomal
dominant
mode ofSGCE
inheritance
with reduced
were superimposed to the abnormal prolonged tonic acpenetrance
consistent
with maternal imprinting. 家系の患
tivity (Fig. 2B). Each patient showing both very short
の重要な原因の
1 つである。本論文では,11
合で認められた。疾患の経過も様々で,運動症状が進
The
mean
age
at
onset
of
the
disease
was
2
years
and
and very long bursts (Fig. 2C,D). The burst occurred
者 20 例に対する臨床的・遺伝的研究結果を報告する。 行する例もあれば自然寛解する例もあった。変異陽性例
4 months (range: 8 months to 3 years). All patients had
mainly synchronous on antagonist muscles (Fig. 2C) but
本研究では,9
家系で
6 つの新規変異ならびに既報告
と変異陰性例の臨床像に明らかな違いはなかった。
a clinical
phenotype
of myoclonus
combined with dyssometimes they were also asynchronous. Other electrotonia, involving the upper body part and being myoclophysiological investigations (somatosensory and central
nus the predominant movement disorder. None of the
motor evoked potentials, long-loop reflex study, EEG–
Movement
Disorders
Vol. 23, No.
1, 2008,
pp. 28-34
patients had an involvement of lower limbs. In one
EMG and
jerked locked
potentials)
resulted
normal
in
family alcohol sensitivity and psychiatric symptoms, deSGCE-positive and -negative patients. In one mutationscribed
as anxiety
disorder were also reported. In both
negative patient (Patient 17), epileptic abnormalities
Key Word
ミオクローヌス・ジストニア,小児,ε
- サルコグリカン遺伝子,臨床像,神経生理学
families there was a history of epilepsy, which did not
characterized by high amplitude spike and waves on
cooccurred in the subjects affected by MDS, with chartemporal regions were transiently recorded on EEG duracteristics of generalized primary epilepsy.
ing sleep.
*
TABLE 3. Polymyographic aspects of myoclonus
Fam.
SGCE
Duration of
No. Pt. No mutation bursts (ms)
1
4
5
6
Pt.
Pt.
Pt.
Pt.
Pt.
Pt.
Pt.
Pt.
Pt.
Pt.
Pt.
1
2
3
4
5
6
8
7
9
10
12
100–500
60–250
100
50–300
80–150
80–200
100–15
60–250
100–200
50–400
100–150
7
8
9
10
Pt.
Pt.
Pt.
Pt.
14
16
17
18
150–400
100–300
100–200
100–300
11
Pt. 20
100–150
2
3
Other characteristics
Synchr, isol
Synchr, arrhyt
Synchr, isol
Synchr, arrhyt
Synchr, isol
Synchr, isol
Synchr, isol
Synchr and asynchr, isol
Synchr, arrhyt
Synchr, arrhyt
Synchr and asynchr,
arrhyt
Synch, arrhyt
Synchr, arrhyt
Synch, arrhyt
Synchr and asynchr,,
arrhyt
Synch, arrhyt
Distribution
Proximal
Proximal
Proximal
Proximal
Proximal
Proximal
Proximal
Proximal
Proximal
Proximal
Proximal
and
and
and
and
and
and
distal
distal
distal
distal
distal
distal
Presence at
rest
Presence with Presence with
postural
voluntary
Stimuli
maintenance
movements
sensitivity
and distal
and distal
and distal
No
No
No
No
No
Yes
No
No
No
Yes
Yes
Yes
Yes
No
No
No
Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Yes
Yes
No
n.t
n.t
n.t
n.t.
Yes
n.t.
Proximal and distal
Proximal and distal
Distal
Proximal and distal
Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
n.t.
Yes
n.t
No
Proximal and distal
Yes
Yes
Yes
n.t
n.t.: not tested; synchr: synchronous; asynchr: asynchronous; isol: isolated; arrhyt: arrhythmic.
Movement Disorders, Vol. 23, No. 1, 2008
15
動作緩慢と固縮を伴うパーキンソン症候群におけるアルギニン
負荷成長ホルモン分泌刺激試験
The Arginine Growth Hormone Stimulation Test in Bradykinetic-Rigid Parkinsonisms
*
Maria Teresa Pellecchia, MD, Katia Longo, MD, Michela Manfredi, MD, Claudio Lucetti, MD, Giovanni Cossu, MD, Alfredo Petrone, MD,
Roberto Marconi, MD, Mariachiara Sensi, MD, Antonio Epifanio, MD, Roberto Eleopra, MD, Roberta Marchese, MD, Tomaso Scaravilli, MD,
Letterio Morgante, MD, Giovanni Abbruzzese, MD, Ubaldo Bonuccelli, MD, Edoardo Donati, MD, Rosario Pivonello, MD, Annamaria Colao,
MD, and Paolo Barone, MD
*
Department of Neurological Sciences, University of Naples “Federico II”, Naples, Italy
アルギニン負荷による成長ホルモン(growth hormone;
PSP 群(6.64 ± 0.82 µg/L)
,対照群(8.59 ± 0.44
GH)分泌刺激試験は,パーキンソン型多系統萎縮症
µg/L)に比べ,MSA-P 群(1.46 ± 0.29 µg/L)で有
(Parkinsonian variant of multiple system atrophy;
。PSP 患者では,PD 患者お
意に低かった(p < 0.01)
MSA-P) と 特 発 性 パ ー キ ン ソ ン 病(Parkinson’
s
よび対照被験者に比べ,GH の最高値が遅れて出現する
disease; PD)との鑑別に有効である。本研究の目的は,
傾向がみられた。カットオフ値を 4 µg/L とした場合,
アルギニン負荷 GH 分泌刺激試験による進行性核上性
アルギニン負荷 GH 分泌刺激試験の PD と MSA-P との
麻 痺(progressive supranuclear palsy; PSP)
,
鑑 別におけ る感 度は 92%,特 異 度は 96 % であり,
MSA-P,PD の 鑑 別 精 度 を 評 価 す る こ と で あ る。
PSP と MSA-P との鑑別における感度は 78%,特異度
MSA-P 患者 26 例,PSP 患者 23 例,PD 患者 26 例,
は 96%であった。アルギニンに対する GH 反応によっ
健常対照被験者 80 例にアルギニンを投与後,血清試料
て,
PD および PSP と MSA-P を高い精度で鑑別できる。
を採取して GH 反応を測定した。GH 濃度とその最高値
PSP 患者のアルギニンに対する神経内分泌反応は,
の群間比較には ANOVA と Bonferroni 検定を用いた。
MSA-P 患者とは異なり正常対照被験者や PD 患者と一
受信者動作特性(ROC)曲線を解析し,MSA-P,PSP,
致しなかった。今回の結果から,GH 分泌を制御する中
PD の鑑別に最も適したアルギニンのカットオフ値を決
枢機構の障害が PSP と MSA-P では異なることが示唆
定した。GH の最高値は,PD 群(8.74 ± 0.98 µg/L)
,
される。
Movement Disorders Vol. 23, No. 2, 2008, pp. 190-194
Key Word 成長ホルモン,アルギニン負荷試験,進行性核上性麻痺,多系統萎縮症
GH levels (µg/l)
20
10
0
PD
PSP
MSA-P
FIG. 2. Distributions of GH peaks after the arginine test in patients
with PD, PSP, or MSA-P. The continuous line indicates the optimum
cut-off value of 4 g/L.
16
パーキンソン病における怒り:症例対照研究
Anger in Parkinson’s Disease: A Case-Control Study
*
Yolanda Macías, PhD, Julián Benito-León MD, PhD, Elan D. Louis MD, MSc, and Antonio Cano-Vindel, PhD
*
Parkinson’s Disease Association of Móstoles, Móstoles, Madrid, Spain
パーキンソン病(Parkinson’
s disease; PD)患者には
向的表出(周りの人や物に怒りをぶつける傾向)
」
(9.0
認知障害/精神症状が高頻度にみられ,運動症状と同
p <0.001)
「怒り表出指数」
,
(26.1
± 2.5対10.5 ± 3.0,
様に日常生活に支障をもたらす。禁欲的で融通の利かな
p = 0.002)のレベルが低く,
「怒
± 8.8 対 29.6 ± 9.4,
い性格特性と PD との関連が指摘されている。これまで
りの内向的表出(怒りを内に秘めたり抑えたりする傾
PD において多くの性格特性に関する研究が行われてき
,
「怒
向)
」
(14.0 ± 3.4 対 12.2 ± 3.2,p < 0.001)
たが,PD における易怒性の性格および怒りの表出性に
りの外向的抑制(周りの人や物に怒りをぶつけるのを抑
関する系統的な研究は行われていない。本研究では,易
えることで怒りをコントロールする傾向)
」
(18.6 ± 5.0
怒性の性格と怒りの表出性を評価するために,6 項目の
,
「怒りの内向的抑制(心
対 16.1 ± 5.0,p < 0.001)
尺度と怒り表出指数(anger expression index)で構成
を落ち着けたり気持ちを冷ましたりすることで怒りをコ
される State-Trait Anger Expression Inventory-2
ントロールする傾向)
」
(14.3 ± 4.7 対 13.0 ± 4.5,p
(ST AXI-2)のスペイン語版を用いた。本研究は,抑う
< 0.05)のレベルが高かった。これらの差は,年齢,
つ症状を伴う 126 例の PD 患者と,年齢および性別を
性別および抑うつ症状について補正した解析でも認め
マッチさせた 126 例の対照被験者を対象とした。PD
られた。結論:PD 患者は,外向的に怒りを表出する傾
患者群は対照群に比べ,
「状況的怒り(感情的になって
向が低く,怒りを抑制する傾向が高かった。今回の結果
いる場面での怒りの強さ)
(
」15.8 ± 3.1 対 17.9 ± 5.3,
により,PD 患者にみられる禁欲的な性格特性の別の側
p < 0.001)
,
「性格的怒り(日頃,怒りを感じる頻度)
」
面が示された。
,
「 怒りの外
(19.2 ± 5.3 対 20.7 ± 6.0,p < 0.05)
Movement Disorders Vol. 23, No. 2, 2008, pp. 195-199
Key Word パーキンソン病,非運動症状,精神医学
ANGER IN PARKINSONS DISEASE
197
TABLE 1. Comparison of demographic and clinical characteristics of PD patients with
depressive symptoms vs. controls
Age in years
Gender (female)
Hoehn and Yahr stage
Disease duration (yr)
Tridimensional depression questionnaire
PD patients (N 126)
Controls (N 126)
P value
67.7 8.9 (69)
63 (50%)
Stage I 3
Stage II 64
Stage III 47
Stage IV 12
6.6 5.2 (5)
52.8 22.5
67.1 9.6 (68)
63 (50%)
Not applicable
0.66a
1.00b
Not applicable
32.4 17.7
0.001a
Results are means SD, and (medians).
a
Mann-Whitney U test.
b 2
test.
6. Anger control-in. This scale assesses the control
of angry feelings by calming down or cooling off
(anger control-in).
7. Anger expression index. This index comes from
which the outcome variables were each one of the
STAXI-2 scores.
The targeted sample size (125–130 participants in
each group) had 93.8 to 94.6% power to detect as little as
17
FREEZING GAIT AND EXECUTIVE FUNCTIONS IN PD
TABLE 1. Demographic and clinical features of PD patients with and without freezing
パーキンソン病患者のすくみ足と遂行機能
Gender (M/F)
FOG (n 13)
FOG (n 15)
P val
9/4
9/6
62.6 8.03
7.53 6.36
5.69 2.25
1.93 0.32
1.07 1.03
5.6 2.77
9.87 3.96
0.6 0.83
28.69 1.15
0.87
0.22
0.77
0.62
0.57
0.71
0.00
0.17
0.07
0.49
627.00 304.68
464.58 247.82
0.42
0.54
Agein Patients with Parkinson’s Disease66.46 8.21
Freezing of Gait and Executive Functions
Beck inventory
8.15 4.47
Disease duration (yr)
5.23 2.52
stage
2.0PhD
0.29
Marianna Amboni, MD, Autilia Cozzolino, MD, KatiaH&Y
Longo,
MD, Marina Picillo, MD, and Paolo Barone, MD,
UPDRS I
1.23 1.30
*
Department of Neurological Sciences, University “Federico II,” Naples, Italy
UPDRS II
10.62 4.21
**
Istituto di Diagnosi e Cura “Hermitage Capodimonte,” Naples, Italy
UPDRS III
12.08 4.42
UPDRS IV
1.54 1.71
MMSE
28.32 1.63
Total equivalent-to-levodopa dosage [levodopa
dopamine agonists] (mg)a
718.46 282.04
Daily levodopa dose (mg)b
522.73 194.12
*, **
Values are mean SD.
All patients were treated with dopamine agonists at commonly used dosages.
b
12/15 FOG patients
and 11/13 FOG patients were also treated with levodopa.
すくみ足(freezing of gait; FOG)はパーキンソン病
認知症または抑うつ症状を伴う患者はいなかった。これ
H&Y stage: Hoehn & Yahr stage; UPDRS: Unified Parkinson’s Disease Rating Scale; MMSE: mini men
(Parkinson’
s disease; PD)患者によくみられる症状
s Disease
state evaluation. らの PD 患者に対し,Unified Parkinson’
a
であり,
運動障害の原因となる。FOG は通常数秒間続く。
Rating Scale(UPDRS)
,FOG 質問票,Mini Mental
shows that
the reduced phonemic verb
FOG patients had pathological
scores
on neuropsychoFOG は短時間の発作性事象で,患者はこの間は歩行動
State
Examination(MMSE)
,frontal
assessment
logical tasks with respect to Italian normative data. In
sample occurred irrespective of disease
作を開始・継続することができない。FOG は高頻度に
battery(FAB)
,音素言語流暢度(phonemic verbal
particular, one patient had subnormal scores on FAB,
Also the mean FAB scores were sign
部,第 ,tenみられる症状であるにもかかわらず,その病態生理は不
Ⅰ
Ⅰ
Ⅰ
Ⅰ
Ⅰ 部)
fluency)検査,Stroop
test(第 Stroop II and III, and TPCT; one
patient on FAB, Stroop
the FOG
patients
than in FOG pa
III,
and
TPCT;
one
on
FAB,
verbal
fluency,
and
TPCT;
subnormal scores,群間
according to Italian n
point clock test(TPCT)による評価を行った。2
明である。前頭葉の機能障害あるいは前頭葉 - 大脳基
one on Stroop III and TPCT; two on FAB and TPCT; one
were found in 6/13 FOG (46.15%)
で UPDRS および MMSE のスコアに差はみられなかっ
底核間の連携離断(disconnection)が FOG に関与す
on TPCT; and one on FAB. In the group of FOG
patients (0%). A significant negative co
の各スコアは,FOG -
ると考えられることから,本研究では神経心理学的検査
patients 3/15 had subnormal た。FAB,言語流暢度,TPCT
scores on TPCT.
FOG score and single FAB subitems w
p=
によって PD 患者の前頭葉機能を検討した。
「薬効 on」 患者よりも FOG +患者で有意に低かった(FAB:
subitems 1 (conceptualization)
and 4 (
DISCUSSION
Surprisingly,
there was no
0.011,TPCT:
p=
0.008, 音 素 言 語 流 暢 度:p =terference).
期にすくみ現象を伴う(FOG +)初期 PD 患者 13 例
Here we demonstrate that on-state FOG is related to
tween motor programming (sub-item 3
0.024)
PD 患者では,FOG
と前頭葉機能試験の
〔Hoehn & Yahr(HY)scale のスコア≦
年齢・
cognitive 2.5〕と,
frontal dysfunction.
Mean。初期
phonemic
verbal
tionnaire score, which is at variance wi
fluency score was significantly
lower in FOG patients
スコア低下との間に関連性が認められた。
HY scale のスコア・罹病期間をマッチさせたすくみ現
freezing is simply due to impaired mot
than
in
FOG
patients.
Verbal
fluency, with both se象を伴わない(FOG -)PD 患者 15 例を対象とした。
We found that FOG patients perf
mantic and phonemic tasks, is associated with frontal
TPCT than FOG subjects. The mean
lobe function. In particular, phonemic verbal fluency,
significantly lower in FOG than in
which requires the ability to suppressMovement
the normal
habit ofVol. 23, No. 3, 2008, pp. 395-400
Disorders
Based
on the arbitrary cutoff suggeste
using words according to their meaning,30 is associated
26 7/13 FOG patients (53.8%
Wu
(7),
to the dorsolateral prefrontal cortex,31-33 anterior cinguKey Word すくみ足,パーキンソン病,遂行機能
mal score; 3/15 FOG patients had sco
late,31,32 and left inferior frontal gyrus.34 Verbal fluency
than the cutoff value. The TPCT serve
35
declines with PD progression. In our study, t-test analgrade cognitive deficits26 and it is se
ysis showed that there was no difference in disease
executive cognitive dysfunctions in peo
duration between and FOG and FOG patients, which
MMSE scores,36 as in our study popula
The mean Stroop part III scores did n
TABLE 2. Cognitive evaluationa
FOG and FOG patients. Individual
normal in 3/13 FOG patients but no
FOG (n 13)
FOG (n 15)
P value
tients. Because Stroop part III evalua
Verbal fluency
29.19 5.97
37.50 9.43
0.011
FAB
14.0 2.16
15.95 1.33
0.008
interference, this result seems to be in
TPCT
5.85 2.70
7.73 1.33
0.024
results of FAB (subitem 4). However,
Stroop II
36.55 8.68
44.67 4.73
0.004
that, besides the orbital and medial fr
Stroop III
18.24 5.3
21.42 3.82
0.077
neural areas are involved in performing
Values are mean SD.
However, although the Stroop test is a “
a
Scores are age and education adjusted.
it is generally agreed that its specificity f
FAB: frontal assessment battery; TPCT: ten-point clock test.
Movement Disorde
18
Abstract
22,00
60,00
20,00
50,00
vflu
fab
18,00
16,00
14,00
40,00
30,00
12,00
20,00
10,00
10,00
0,00
5,00
10,00
15,00
20,00
0,00
5,00
60,00
10,00
50,00
8,00
40,00
6,00
30,00
2,00
10,00
0,00
5,00
10,00
fogquest
15,00
20,00
15,00
20,00
4,00
20,00
0,00
10,00
fogquest
tpct
stroop2
fogquest
15,00
20,00
0,00
5,00
10,00
fogquest
FIG. 1. Correlations between FOG-Questionnaire (fogquest) scores and FAB (fab), verbal fluency (vflu), Stroop II (stroop2), and TPCT (tpct) scores.
Squares: FOG ; Circles: FOG .
19
パーキンソン病患者の意思決定:Iowa Gambling Task によ
る行動および生理学的パターンの解析
Decision Making in Parkinson’s Disease: Analysis of Behavioral and Physiological Patterns in the
Iowa Gambling Task
*
Mutsutaka Kobayakawa, PhD, Shinichi Koyama, PhD, Masaru Mimura, MD, and Mitsuru Kawamura, MD
*
Department of Neurology, Showa University School of Medicine, Tokyo, Japan
最 近 の 研 究 で は, パ ー キ ン ソ ン 病(Parkinson’
s
び報酬や罰金を受けた後の SCR は,NC 被験者よりも
disease; PD)に伴う社会的認知機能の障害が報告され
PD 患者で低かった。PD 患者が高リスクの選択を行う
ている。しかし,これに伴って PD 患者の行動に異常が
傾向は,年齢,学歴,全般的な認知機能,PD 重症度と
生じるかどうかについては,なお議論の余地がある。本
は相関しなかった。以上の結果から,PD 患者の意思決
研究の目的は,Iowa Gambling Task(IGT)を用いて
定は,他の認知機能よりも,むしろ疾患そのものに影響
PD 患者の意思決定を検討することである。認知症を伴
を受けており,PD 患者の高リスク行動には感情的反応
わない初期 PD 患者を多数募集し,
IGT を実施した。また,
の乏しさが関連していることが確認された。PD 患者の
感情的興奮の尺度として,IGT 実施中に皮膚コンダクタ
行動および SCR のパターンは,扁桃体に障害のある患
ンス反応(skin conductance response; SCR)を記録
者と類似していた。PD 患者にみられる高リスクを選択
し た。IGT に お い て,PD 患 者 は 健 常 対 照(normal
する傾向は,扁桃体(リスク判断への関与が知られてい
control; NC)被験者に比べ,リスクの高い不利なカー
る)の機能障害により説明できると考えられる。
ドの山を選択する傾向にあった。また,意思決定前およ
Movement Disorders Vol. 23, No. 4, 2008, pp. 547-552
Key Word 意思決定,Iowa Gambling Task,皮膚コンダクタンス反応,社会的認知機能,パーキンソン病
20
Abstract
A
B
C
IGT scores for each block (C+D)-(A+B)
7
250000
200000
Total IGT Scores (C+D)-(A+B)
Total Gain (yen)
15
150000
100000
50000
10
5
0
-5
-10
-15
-20
-25
0
PD
6
5
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
PD
NC
1-20
NC
21-40
41-60
PD
61-80 81-100
Trail#
NC
FIG. 1. Results from the Iowa Gambling Task. Significant differences were observed between the amount made by PD patients and that made by
the normal control subjects (A). The total IGT scores (B) and IGT scores for each block of 20 card selections (C) were significantly different. PD
patients chose risky decks significantly more frequently than the NC subjects.
Reward SCR
0.4
0.3
0.35
0.25
0.3
0.2
0.25
SCRs (µS)
0.35
0.15
0.1
0.6
0.5
0.4
0.2
0.15
0.1
0.05
0
Punishment SCR
SCRs (µS)
Anticipatory SCR
SCRs (µS)
C
B
A
NC
0
0.2
0.1
0.05
PD
0.3
0
PD
NC
PD
NC
Advantageous Decks (C & D)
Advantageous Decks (C & D)
Advantageous Decks (C & D)
Disadvantageous Decks (A & B)
Disadvantageous Decks (A & B)
Disadvantageous Decks (A & B)
FIG. 2. Results from the SCR analysis. PD patients generated lower anticipatory (A), reward (B), and punishment (C) SCRs than the NC subjects.
21
パーキンソン病における反復経頭蓋磁気刺激の治療効果:
11
C-raclopride PET による解析
Therapeutic Effect of Repetitive Transcranial Magnetic Stimulation in Parkinson’s Disease: Analysis
of [11C] Raclopride PET Study
*
Ji Youn Kim, MD, Eun Joo Chung, MD, Won Yong Lee, MD, PhD, Hee Young Shin, MD, Gyeong Han Lee, MD, PhD, Yearn-Seong Choe, MD,
PhD, Yong Choi, PhD, and Byeong Joon Kim, MD, PhD
*
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
反復経頭蓋磁気刺激(repetitive transcranial magnetic
を 2 回にわたり,症状が強い側の運動皮質(motor
stimulation; rTMS)は,パーキンソン病(Parkinson’
s
cortex; MC)の手指領域に実施した。MC への一側
disease; PD)に有効な治療手段として使用されてきた。
rTMS 施 行 後, 平 均 raclopride 結 合 能(binding
しかし,PD に対する rTMS の治療上の価値および/ま
potential; BP)は,刺激側の被殻および尾状核領域だ
たはプラセボ効果については,まだ明らかになっていな
,
けでなく
(それぞれ-4.9%および-6.5%)
(p >0.05)
い。PD における rTMS の治療上の価値および/または
非刺激半球の被殻および尾状核領域でも低下していた
プラセボ効果を検討するため,PD 患者 9 例に rTMS を
(それぞれ- 6.6%,p > 0.05 および- 12.1%,p =
2 回実施し,その前後で Unified Parkinson’
s Disease
0.049)
。UPDRS PartⅠ
(運動)のスコアは有意に低下
Ⅰ
Ⅰ
Rating Scale(UPDRS)PartⅠ
(運動)のスコアおよび
Ⅰ
Ⅰ
していた(35.0 ± 14.1 から 32.0 ± 13.4 に低下,p
11
C-raclopride PET による総細胞外ドパミン濃度を比
= 0.049)
。一側 rTMS により非刺激側の腹側線条体に
較した。薬効 off 期の連続 2 日間,周波数 5 Hz の刺激
おいて raclopride BP が低下したことから,rTMS 施行
15 回からなる rTMS(強度:安静時運動閾値の 90%)
中にプラセボ反応が生じることが示された。
Movement Disorders Vol. 23, No. 2, 2008, pp. 207-211
Key Word 反復経頭蓋磁気刺激,11C-raclopride PET,パーキンソン病,プラセボ効果
22
Abstract
208
J.Y. KIM ET AL.
TABLE 1.
Subjects
Age (yr)
Disease duration (yr)
H-Y stage
Medication
1
2
3
Female
Male
Male
53
64
54
6
2
6
Left
Right
Left
2
1
2
4
5
6
Female
Male
Male
40
67
68
2
11
6
Left
Right
Left
2
3
2
7
Male
43
3
Left
2
8
Female
53
8
Right
2
9
Female
60
4
Left
3
Drug naive
Ropinirole, 3 mg/day
Levodopa, 600 mg/day
Ropinirole, 3 mg/day
Levodopa, 300 mg/day
Levodopa, 600 mg/day
Levodopa, 450 mg/day
Ropinirole, 6 mg/day
Levodopa, 300 mg/day
Ropinirole, 3 mg/day
Levodopa, 150 mg/day
Ropinirole, 1.5 mg/day
Levodopa, 300 mg/day
Ropinirole, 3 mg/day
55.8 10.0
5.3 3.0
Mean SD
Sex
Clinical data of the enrolled Parkinson’s disease patients
Male: 5
Female: 4
More affected side
Right: 3
Left: 6
2.1 0.5
H-Y stage, Hoehn and Yahr stage.
SD, standard deviation.
1. Following overnight withdrawal of antiparkinsonian
medication, motor sections of unified PD rating scale
(UPDRS III) scores11 were evaluated and [11C] raclopride PET scans were performed to provide baseline
data. Within 24 hours after baseline raclopride PET
scans, participants underwent the first session of rTMS to
10
the contralateral side of MC to the more severely af8
fected extremities, i.e., showing severe
rigidity, bradykinesia, or resting tremor (hereafter referred
to as the more
6
severely symptomatic hemisphere). The following day,
4
the second session of rTMS was administered. Antiparkinsonian medication was withdrawn
throughout the
2
study. Immediately after the second stimulation, UPDRS
0
baseline
rTMS werebaseline
study
car- rTMS
III scores and the [11C] raclopride PET
stim-putamen
stim-caudate
ried out to provide poststimulation data.
[11C] Raclopride PET Scans
% change RAC BP
[11C] RAC BF
PET scans were performed in three-dimensional (3D)
mode using an Advance PET scanner (GE Medical Systems, Milwaukee, WI) with an average in-plane resolution of 4.5-mm full width at half-maximum. Patients
were positioned in the scanner with heads aligned parallel to the orbitomental line using a laser beam. Transmission scans for attenuation correction were obtained
over 10 minutes using a rotating 68Ge rod before emission scan acquisitions. At the start of each PET scan (the
baseline data, before rTMS; the poststimulation data, 5
minutes after the end of the second rTMS session),
patients received a slow bolus intravenous injection of
baseline
baseline[11
rTMS
C] of raclopride. Sequential 28
from
10 rTMS
to 20 mCi
non-stim-putamen
non-stim-caudate
emission
scan frames
of increasing length were then
acquired over 60 minutes starting at the time of injection.
0
All emission scans were reconstructed using 3D filtered
Repetitive Transcranial Magnetic
Stimulation
-5
back projection using a Hamming filter.
rTMS was carried out using a Magstim
stimulator (2.2
-10
Raclopride binding potentials (BPs) of the caudate and
T) through a figure-eight coil during
off-medication on 2
-15
putamen
were extracted with spherical regions of interconsecutive days. TMS was delivered through a figure-20
ests
and
calculated using a simplified reference tissue
eight coil oriented so that the induced electrical current
-25
(cerebellum)
method to measure changes in BP.12,13 A
flowed in a posterior–anterior direction over the hand
FIG. 1. On the top, [11C] raclopride
BP (baseline
and
reduction
in
[11
C]following
raclopride BP in the caudate and
area of MC corresponding to rTMS),
more from
severely
affected
the caudate
and putamen of the stimulated and nonstimuputaminal
areas
after
to the MC suggests an inextremities. rTMS intensities were
90%
of resting
motor with spherical regions of interestsrTMS
lated
hemispheres,
extracted
and
crease
in
the
amount
of
intrinsic
striatal dopamine.
calculated
usingwhich
a simplified
threshold for the abductor pollicis
brevis,
wasreference tissue (cerebellum) method to
measure changes in BP. On the bottom, the figure displays the per-
determined as the minimum intensity
that produced
at
centage changes
in [11C] raclopride
BP for the stimulated (black bar)
least five motor evoked potentials
amplitude(gray
exceedandof
nonstimulated
bar) hemispheres. The magnitude ofStatistical
change in Analysis
was significant
in the caudate All
of nonstimulated
hemisphere
ing 100 V. rTMS blocks werebinding
delivered
10 minutes
data are presented as mean standard deviation.
(P 0.05 by Wilcoxon signed rank test).
apart in the scanner prior to image acquisition. During
SPSS (version 12.0) for Windows (SPSS, Chicago, IL)
each of the two sessions, each block consisted of 15
was used for the statistical analysis. The Wilcoxon
5-pulse trains of 1 second duration (i.e. 5 Hz) with
signed rank test was used to assess differences in raclopride BPs and part III UPDRS scores before and after
intertrain intervals of 10 seconds.
Movement Disorders, Vol. 23, No. 2, 2008
23
パーキンソン病患者における鏡像運動
Mirror Movements in Patients with Parkinson’s Disease
*
Donatella Ottaviani, MD, Dorina Tiple, MD, Antonio Suppa, MD, Carlo Colosimo, MD, Giovanni Fabbrini, MD, Massimo Cincotta, MD, Giovanni Defazio, MD, and Alfredo Berardelli, MD
*
Department of Neurological Sciences and Neuromed Institute (IRCCS), “La Sapienza” University of Rome, Rome, Italy
鏡像運動(mirror movement; MM)とは,一側の随意
に一側性であった。パーキンソン徴侯が一側性の場合,
運動時に反対側の同一身体領域にみられる不随意運動
MM は常に健側に生じ,パーキンソン徴侯が両側性の場
の こ と で あ る。 本 研 究 の 目 的 は,パ ー キ ン ソ ン 病
合,MM は障害の弱い側に認められた。MM がみられ
(Parkinson’
s disease; PD)患者 274 例および健常被
た PD 患者は,MM のない患者に比べ,Hohen and
験者 100 例の任意抽出サンプルにおいて MM の発現頻
Yahr(HY)分類のスコアが有意に低かった。同様に,
度と分布を比較し,MM と PD 臨床像との関連性を検討
Woods and Teuber scale のスコアで判定した MM の
することである。手部の MM を Woods and Teuber
程度と HY 分類の間にも,有意な逆相関が認められた(r
scale に従ってスコア化した。MM の発現頻度は,PD
。PD 患者ではおそらく,パーキ
=- 0.16,p < 0.01)
患者の方が健常被験者よりも低かった(29%対 71%,
ンソン徴侯をもたらす病態生理学的機序と運動の左右
p < 0.0001)
。MM の分布も両群で異なり,健常被験
差が生じる機序とが複雑に相互作用し,これに伴い MM
者群では両側性の場合が多かったが,PD 患者群では常
の発現頻度が低くなっていると考えられる。
Movement Disorders Vol. 23, No. 2, 2008, pp. 253-258
Key Word 運動系,運動,パーキンソン病
24
NTS WITH PARKINSONS DISEASE
or both
M.
der, PD
healthy
wer freand sex
tion beds ratio
3; P subjects
nsonian
on the
bilateral,
fingers tasks
Teuber
le 2). In
d more
healthy
ale gave
in both
gnificant
ge (r und with
were obWoods
y higher
whereas
ures did
MM. In
patients
56/173
disease
nts with
sidering
mirror
healthy
P
value
0.001
0.27
0.0001
0.0001
ann-Whit-
Abstract
255
TABLE 2. Distribution of the Woods and Teuber scale
scores for mirror movements in the various tasks in patients
with Parkinson’s disease and healthy subjects
Woods and Teuber scale
Task 1: tapping the thumb
against the index finger
Score 1
Score 2
Score 3
Score 4
Task 2: finger-thumb opposition
Score 1
Score 2
Score 3
Score 4
Task 3: hand opening-closing
Score 1
Score 2
Score 3
Score 4
Task 4: First dorsal interosseous
muscle isometric
contraction
Score 1
Score 2
Score 3
Score 4
Parkinsonian
patients
Healthy
subjects
29
4
0
0
32
12
0
0
51
17
0
0
74
35
3
0
29
11
6
1
37
8
0
0
22
6
0
0
19
8
1
0
P
0.16
0.24
0.02
0.32
2 test(Fisher exact test when appropriate).
patients staging 4 –5 on the HY scale as a reference, and
adjusting for age, sex, duration of disease, and presence
of clinical fluctuations/dyskinesias, there was a significant association of MM with both PD patients staging
1–1.5 (adjusted OR, 5.3; 95% confidence interval, 1.2–
23; P 0.025) and PD patients staging 2–3 (adjusted
OR, 5.4; 95% confidence interval, 1.5–19; P 0.009).
None of the adjusted ORs for the other examined parkinsonian features reached the level of statistical significance (data not shown).
In the PD population, there was a significant inverse
correlation between the overall Woods and Teuber score
and HY staging (r 0.16, P 0.01) and disease
duration (r 0.15, P 0.02). No correlation was
observed with age (r 0.09, P 0.13), sex (r 0.01,
P 0.86), and presence of clinical fluctuations (r 0.05, P 0.4) or dyskinesias (r 0.09, P 0.13).
Similar findings were observed when considering the
various tasks of the Woods and Teuber score separately
(not shown).
EMG Study
ANOVA with “Group”, “APB performing movement”
and “APB at rest” as main factors of analysis showed no
significant effect of factor “Group” (F(2,27) 0,81; P 0.46) demonstrating that for both hands EMG back-
Movement Disorders, Vol. 23, No. 2, 2008
256
D. OTTAVIANI ET AL
TABLE 3. Demographic and clinical characteristics of
Parkinson’s disease patients with and without mirror
movements
Number
Sex (men/women)
Mean age (years) SD
Mean disease duration (years)
SD
UPDRS (mean SD)
Tremor
Rigidity
Bradykinesia
Hoehn-Yahr staging (%)
1
1.5
2
2.5
3
4
5
Mean SD
Levodopa treatment
Number of patients (%)
Daily dose (mg)
Duration (months)
Dopamine agonist treatment
Number of patients (%)
Duration
Motor fluctuations (%)
Dyskinesia (%)
Parkinson’s
disease
patients
with mirror
movements
Parkinson’s
disease
patients
without
mirror
movements
P values
76
45/31
67.6 8.2
186
108/78
69.3 9.3
0.86
0.17
6.9 5.7
8.3 5.7
0.072
2.9 3
6.1 2.7
10.3 4.5
3.1 3.3
6.1 3.2
10.7 4.9
0.34
0.43
0.53
9 (12%)
8 (10%)
29 (38%)
14 (18%)
13 (17%)
3 (4%)
0 (0%)
3.3 1.3
15 (8%)
17 (9%)
61 (33%)
20 (11%)
36 (19%)
33 (18%)
4 (2%)
3.9 1.5
57 (75%)
518 269
67 67
150 (80%)
567 290
78 66
0.31
0.27
0.29
40 (52%)
39 46
30 (39%)
18 (24%)
85 (46%)
34 45
82 (44%)
63 (34%)
0.31
0.52
0.5
0.32
0.042
0.003
P by 2 test(Fisher’s exact test when appropriate) and Mann-Whitney U test.
ground was similar in both APB muscles and in all
groups of subjects. Between-group ANOVA with
“Group” and “APB performing movement” as main factors of analysis testing EMG mirror showed a significant
mirror A
significa
in healt
Ratio m
patients
with MM
MMclin;
MMclin
P 0.01
vs. ratio
0.74).
This i
MM as
healthy
found a
in case p
No prior
unselect
reliable
subjects.
increase
ing age.
creased
age in o
The fr
ering all
reported
of PD p
ease.13,14
unilatera
an inver
mirrorin
25subjects,
tients M
パーキンソン病における衝動性と衝動制御障害の関連性
The Relationship Between Impulsivity and Impulse Control Disorders in Parkinson’s Disease
*
Ioannis U. Isaias, MD, Chiara Siri, PhD, Roberto Cilia, MD, Danilo De Gaspari, MS, Gianni Pezzoli, MD, and Angelo Antonini, MD
*
Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy
パーキンソン病(Parkinson’
s disease; PD)患者では,
対 照 被 験 者 の 20 %(20/100 例 ) で,MIDI ま た は
ドパミン作動性薬剤に関連して様々な行動障害が起こる
SOGS スコアに衝動制御障害を示す異常行動が 1 つ以
と考えられ,近年この問題が認識されるようになってい
,
強迫性
(p <0.001)
,
上認められた。衝動性
(p =0.006)
る。本研究では,安定用量のドパミンアゴニストおよび
抑うつ(p < 0.001)のスコアは,対照群よりも PD 群
レボドパ(L—ドパ)投与を受け,認知機能が正常である
で高かった。PD 群において衝動性,強迫性,抑うつの
連続した PD 患者 50 例と健常対照被験者 100 例を対
各スコアの相関性は認められなかった。PD 群では,男
象に,強迫的な性行動・強迫的買物行動・間欠性爆発性
性で衝動性スコア高値の場合に MIDI で衝動制御障害と
障害は Minnesota Impulsive Disorders Interview
(MIDI)
判定される確率が上昇したが,ドパミン作動性薬剤の用
で,
病的賭博は South Oaks Gambling Screen(SOGS)
量や種類との間に関連は認められなかった。衝動制御
で,衝動性は Barratt Impulsiveness Scale で,強迫性
障害は対照群でも多くみられた。高い衝動性や抑うつと
は Maudsley Obsessional-Compulsive Inventory で,
いった患者個人の感受性因子により,安定したドパミン
抑うつは Geriatric Depression Scale でそれぞれ評価し
補充療法を受ける PD 患者の異常行動が増加すると考え
た。全体として,PD 患者の 28%(14/50 例)と健常
られる。
Movement Disorders Vol. 23, No. 3, 2008, pp. 411-415
Key Word パーキンソン病,衝動制御障害,衝動性,強迫性
26
Abstract
IMPULSE CONTROL DISORDERS IN PD
413
TABLE 1. Number of PD patients and healthy controls
(male patients in brackets) with ICDs and domain
distribution
11A was higher in both PD men and women with ICDs
IMPULSE CONTROL DISORDERS IN PD
(Table 2).
In the healthy control cohort (Table 2) BIS-11A and
Number of PD patients
and scores
healthywere
controls
ICDs scales
PD TABLE 1.
Controls
11A was
higher
both PD men and w
GDS-15
higher in subjects
with
ICDs.inHow(male patients in brackets) ever,
with ICDs
andrelated
domaindifferences were
(Table
2). only for men
gender
found
MIDI CB
5 (1)
9 (1)
distribution
MIDI ED
1
6 (2)
In the healthy control cohort (Table
but not for women.
MIDI CS
2 (1)
1
(1)
ICDs scales
PD
Controls
GDS-15
scores
were higher
in subjects w
All
subjects
were
classified
as
having
a PS below
or
SOGS
1
1
ever,balance
gender related
were fou
above
of PD differences
and
CB CS
2 (2)
MIDI CB0
5 (1) the median.
9 (1) Given the good
CB ED
1 (1)
MIDI ED1 (1)
1
6 (2)
but not sub-sample,
for women. this
healthy
controls
in the above-median
ED CS
0
MIDI CS1 (1)
2 (1)
1 (1)
subjects the
weretwo
classified as havin
was
preferred 1 for comparisonsAllbetween
CB CS ED
0
SOGS 1 (1)
1
CB CS SOGS
1 (1)
above
the
median.
Given
CB CS0
2
(2)
0
groups. In this sub-sample the incidence of ICDs was the good bal
CB ED SOGS
1 (1)
CB ED0
1 (1)
(1)
in The
the above-median s
35.1%
in PD 11 and
20.6% in healthy
healthy controls
controls.
ED CS
0
(1)
was (14.5%;
preferred
comparisons bet
difference
between
P for
0.17)
MIDI, Minnesota Impulsive Disorders Interview;
compulsive
CB CB,
CS ED
0
1 (1) the two groups
buying; ED, intermittent explosive disorder; CS,
sexual
CB compulsive
CS SOGS
1 (1) magnified0 with respect togroups.
In this sub-sample
the inciden
was
that observed
in the
behavior; SOGS, South Oaks Gambling Screen:
gamCB (pathological
ED SOGS
1 (1)
0
35.1%
in
PD
and
20.6%
in healthy
overall
sample
(8%),
even
though
in
both
cases
the
bling).
difference
between
the two groups (14
MIDI, Minnesota Impulsive Disorders
Interview;
CB, size
compulsive
limited
sample
did not allow
to reach
statistical
buying; ED, intermittent explosive disorder; CS, compulsive sexual
was magnified with respect to that o
significance.
behavior; SOGS, South Oaks Gambling Screen: (pathological gamoverall in
sample
(8%), even though in
The
logistic
regression
performed
PD patients
bling). at multiple ICDs,
subjects (3/20%–15%) were positive
limited
sample
size
did not allow to
showed
male
gender
and
higher
BIS-11A
score
as the
all of them were men (Table 1).
significance.
only
factors
associated
with
increased
probability
of
ocAmong ICD positive PD patients, 8 were taking
regression performed
currenceatofmultiple
at least one
ICD. On theThe
basislogistic
of the resulting
pramipexole of a total of 32 patients,
ropinirole of 4were positive
subjects1 (3/20%–15%)
ICDs,
showed
male
gender
and higher BIS-1
model, we calculated a cut-off value for BIS-11A (score
patients, 4 cabergoline of 11 patients,
pergolide
all of and
them1 were
men of
(Table 1).
only
factors
associated
When
applied
to PD, this cut-off selected 33with increased p
3 patients.
Among ICD positive PD 44).
patients,
8 were
taking
currence
at least
oneinICD. On the basi
patients (66%)
including
patientsofwith
ICDs
BIS-11A and GDS-15 scores pramipexole
were higher in
withof 32 patients,
of PD
a total
1 ropinirole
of 412 of 14
model, we calculated a cut-off value for
the whole
group (85%).
ICDs while MOCI did not differ.
In addition
the BIS-of 11 patients,
patients,
4 cabergoline
andPD
1 pergolide
of
44). When applied to PD, this cut3 patients.
patients (66%) including 12 of 14 patien
BIS-11A and GDS-15 scores were higher in PD with
the disorders
whole PD group (85%).
Table 2. Parkinson’s ICDs
diseasewhile
patients
and healthy
and without
MOCI
did notcontrols
differ. with
In addition
the impulse
BIS- control
PD patients
Men, no (%)
Age (yr)
Education (yr)
BIS–11A
BIS–11A men
BIS–11A women
GDS–15
MOCI
PD duration (yr)
Total LEDD (mg/day)
Time on therapy (mo)
UPDRS III
All patients
(n 50)
ICDs positive (n 14)
ICDs negative (n 36)
P value
Table7 (50%)
2. Parkinson’s disease patients
and healthy controls with and
without impulse control disor
24 (67%)
0.02
31 (62%)
65 (9)
60 (9)
47–76
65 (9)
51–80
0.04
All patients
9 (4)
10 (5)
5–17
9 (4) ICDs positive5–17
0.64 ICDs negative (n 36)
PD patients
(n 50)
(n 14)
50.4 (11.7)
57.5 (10)
38–75
47.6 (11.3)
32–76
0.006
53 (11) Men, no61.1
53–75
30–76
0.0224 (67%)
(%) (7)
31 (62%) 50.7 (11)
7 (50%)
45 (11) Age (yr)53.8 (11.7)
38–70
41.2 (9.1)
32–347–76
0.0265 (9)
65 (9)
60 (9)
51–80
4.3 (3.4)Education6.0
1–139 (4)
3.6 (3)
0–125–17
0.02 9 (4)
(yr)(3.7)
10 (5)
5–17
7 (5) BIS–11A 8.5 (4)
3–16
(5.3)(10)
0–19
0.247.6 (11.3)
50.4 (11.7) 6.557.5
38–75
32–76
9 (5) BIS–11A men
9 (5)
4–24
861.1
(5) (7)
1–26
0.69
53 (11)
53–75
50.7 (11)
30–76
631 (280)BIS–11A656
(252)
290–1250
62253.8
(294)(11.7)
250–1205
0.741.2 (9.1)
women
45 (11)
38–70
32–3
71.7 (63.7)
13–286
73 (61)
12–312
0.8 3.6 (3)
GDS–15 68 (71)
4.3 (3.4)
6.0 (3.7)
1–13
0–12
18.2 (6.3)MOCI 16.7 (6)
6–267 (5)
18.8 (6.4)
5–303–16
0.3 6.5 (5.3)
8.5 (4)
0–19
PD duration (yr)
9 (5)
9 (5)
4–24
8 (5)
1–26
Total LEDD (mg/day)
631 (280)
656 (252)
290–1250
622 (294)
250–1205
All subjects
Time on therapy
68 negative
(71)
13–286
73 (61)
12–312
Healthy controls
(n 100)
ICDs (mo)
positive (n 71.7
20) (63.7)
ICDs
(n 80)
P value
UPDRS III
18.2 (6.3)
16.7 (6)
6–26
18.8 (6.4)
5–30
Men, no (%)
47 (47%)
7 (35%)
40 (50%)
0.3
Age (yr)
61 (9)
55 (7)
41–67
63 (9)
40–80
0.001
All subjects
Education (yr)
11 (5)
(5)
5–17
10 (5) ICDs positive 5–17
0.14 ICDs negative (n 80)
Healthy12controls
(n 100)
(n 20)
BIS–11A
46 (9.5)
51.2 (9)
36–66
44.1 (9.3)
32–67
0.003
BIS–11A men
44.7 (9.7)Men, no53.3
36–58
31–64
0.007
(%) (7.8)
47 (47%) 43.3 (8.7)
7 (35%)
40 (50%)
BIS–11A women
47 (9.2)Age (yr)50.1 (9.5)
40–66
46.0 (9.7)
32–67
0.1963 (9)
61 (9)
55 (7)
41–67
40–80
GDS–15
2.5 (2.6)Education3.8
0–9
2 (2.5)
0–135–17
0.008
(yr)(2.8)
11 (5)
12 (5)
10 (5)
5–17
MOCI
3.7 (3.8)BIS–11A
n.a.
n.a.
46 (9.5)
51.2 (9)
36–66
44.1 (9.3)
32–67
BIS–11A men
44.7 (9.7)
53.3 (7.8)
36–58
43.3 (8.7)
31–64
Values are expressed as mean, standard
deviation,
and range (unless otherwise
P values refer to
ICDs positive46.0
vs. (9.7)
BIS–11A
women
47 (9.2) indicated);
50.1 (9.5)
40–66
32–67
negative sub-scores.
GDS–15
2.5 (2.6)
3.8 (2.8)
0–9
2 (2.5)
0–13
Abbreviations are described in the text.
MOCI
3.7 (3.8)
n.a.
n.a.
Values are expressed as mean, standard deviation, and range (unless otherwise indicated); P values refer to ICDs
negative sub-scores.
Abbreviations are described in the text.
Movement Disorders, Vol. 23, No. 3, 2008
Movement Disorder
27
パーキンソン病患者の深部脳刺激に関する多施設共同試験:
術後 4 年時点における有害事象報告の独立評価
Multicenter Study on Deep Brain Stimulation in Parkinson’s Disease: An Independent Assessment of
Reported Adverse Events at 4 Years
*, **
Marwan I. Hariz, MD, PhD, Stig Rehncrona, MD, PhD, Niall P. Quinn, MD, Johannes D. Speelman, MD, PhD, Carin Wensing, and the Multicentre Advanced Parkinson’s Disease Deep Brain Stimulation Group
*
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, United Kingdom
Department of Neurosurgery, University Hospital, Umeå, Sweden
**
8 施設による多施設共同試験で,
視床下核(subthalamic
DBS を受けた患者の 35%で 8 件報告された。AE の多
nucleus; STN)
(49 例)または淡蒼球内節(internal
くは重度とは判定されず,
「刺激時と非刺激時の両方で」
globus pallidus; GPi)
(20 例)への深部脳刺激(deep
発現することが報告されていた。AE の大部分は,発語,
brain stimulation; DBS)を受けた進行期パーキンソン
歩行,バランスばかりでなく,認知・精神・行動機能に
病(Parkinson’
s disease; PD)患者 69 例を対象に,
も影響を与え,それらの多くは STN DBS を受けた患者
術後 4 年で認められる持続的な有害事象(adverse
に認められた。AE が発現した患者と発現しなかった患
event; AE)を独立した専門委員会が解析した。ベース
者を比較すると,STN DBS 群では,AE を発現した患
ライン時には患者の年齢,性別,罹病期間,病状にほと
者は罹病期間が長く,ベースライン時における歩行障害
んど差はみられず,追跡調査期間中も同様であった。
と精神障害がより高度であった。
AE は STN DBS を受けた患者の 53%で 64 件,GPi-
Movement Disorders Vol. 23, No. 3, 2008, pp. 416-421
Key Word 有害事象,深部脳刺激,淡蒼球,パーキンソン病,視床下核
28
Abstract
M.I. HARIZ ET AL.
where no evidence of normal distribuFor this reason, the test used was always
c Wilcoxon (Mann–Whitney) test. All
ne using SAS software version 8.02 or
variables, counts were presented torelative frequencies as percentages. A
ered significant when the accompanyless than 0.05.
RESULTS
the results of DBS with respect to
mptoms and signs, it is referred to the
paper.2 In summary, at 4-years followon unified Parkinson’s disease rating
art III (motor scores) had improved in
ts by 50% and in GPi DBS patients by
ith baseline. Dopaminergic medication
y in the STN DBS group. Dyskinesias
antly in both groups.
e-Related Adverse Events
S patients and one GPi DBS patient
al surgery to treat device-related comfracture, infection of the connection
n erosion, or infection at the site of the
atients, infection of the device led to
f DBS. During the follow-up period, 6
patients (12.2%) and eight of 20 GPi
%) had stimulator replacement because
life, which may be an expression of the
n parameters used in the GPi group.2
TABLE 2. Distribution and details of adverse events (AEs)
at 4 years in patients with STN and GPi DBS
No of patients
No. (%) of patients with AE
Total no. of AE
Cognition/memory decline, psychiatric
disturbances
Depression/apathy/anxiety mood
disturbance
Hypersexuality
Speech
difficulties/dysphonia/dysarthria
Dysphagia
Dysequilibrium/falls/balance
disturbances
Gait disorders
Dystonia/cramps/pain/tightness
Dyskinesias
Sleep disorders
Increased PD symptoms
Motor fluctuations
Weakness/fatigue/decreased endurance
Eyelid-opening apraxia
Drooling
Orthostatism
Double vision
Pain
Paresis
Bone fracture
STN DBS
GPi DBS
49
26 (53%)
64
20
7 (35%)
8
No. of AE
(%)
No. of AE
(%)
12 (18.8)
1 (12.5)
3 (4.7)
1 (1.5)
0
1 (12.5)
9 (14.1)
3 (4.7)
1 (12.5)
0
8 (12.5)
9 (14.1)
1 (1.5)
1 (1.5)
2 (3.1)
1 (1.5)
1 (1.5)
2 (3.1)
2 (3.1)
2 (3.1)
1 (1.5)
1 (1.5)
2 (3.1)
1 (1.5)
2 (3.1)
0
0
1 (12.5)
1 (12.5)
1 (12.5)
1 (12.5)
0
0
1 (12.5)
0
0
0
0
0
0
chosen by clinicians to receive GPi DBS had more severe dyskinesias than those selected for STN DBS. At
ADVERSE EVENTS OF DBS IN STN AND GPI
4-years follow-up, levodopa equivalent doses were sigvice-Related Adverse Events
nificantly (P 0.0001) higher in patients with GPi DBS
orty-nine (53%) STN DBS
patients
had
TABLE
3. Distribution
of the
events
(AEs)
in patients with STN and GPi DBS, according to severity
than
in adverse
those with
STN
DBS.
, and 7 of 20 (35%) GPi patients had a
STN patients
GPi patients
Comparison Between Patients
with and Without
s. In both groups, the majority of the
Adverse Events
Mild
Moderate
Severe
Mild
Moderate
reported as being unrelated to stimulaNo. (%)
No. (%)
No. (%)
No. (%)
No. (%)
nt both with and without stimulation.”
The characteristics of patients who developed AEs as
Cognition/memory
decline,
psychiatric
disturbances
4
(8)
7
(14.3)
1
(2)
1
(5)
0
f follow-up visits varied considerably
compared with those who did not were analyzed in both
Depression/apathy/anxiety mood disturbance
0
3 (6)
0
0
0
Also, the various
AEs (that were by
groups with respect0 to age, response
to L-dopa
Hypersexuality
0
1 (2)at base- 1 (5)
0
going at 4 years)
appeared
at a variable
line, axial symptoms
(rising from
Speech
difficulties/dysphonia/dysarthria
2 (4)
3 (6) chair, postural
4 (8) stabil- 0
0
Dysphagia
1 (2)swallowing),
1 (2) and with1 (2)
0
gery (mean 673
days postoperatively,
ity, gait, speech, and
respect to 0
Dysequilibrium/falls/balance disturbances
2 (4)
5 (10.2)
1 (2)
0
0
239 –1527 days).
Table 2 shows the
items of UPDRS part
Gait disorders
2 (4)I. There 3was
(6) no difference
4 (8) in age 0
0
mber, and percentage
of AEs for each
between patients with
with patients
with- 0
Dystonia/cramps/pain/tightness
1 (2)AEs compared
0
0
0
Dyskinesias
0
1 (2) in the STN
0
0
ble 3 shows the
distribution of AEs in
out AEs in either group.
However,
group, 0
Sleep disorders
1 (2)
1 (2)
0
0
1 (5)
p according toIncreased
the severity
of the AE.
depression, thought 0disorders, rising
from chair
PD symptoms
0
1 (2)and gait 0
0
were more affected at
those patients
Motor fluctuations
0 baseline in
1 (2)
0 who later 0
0
etween Patients
with STN DBS andenduranceexhibited AEs at 4-years
Weakness/fatigue/decreased
1 (2) follow-up.
1 (2) Furthermore,
0
0
in the 0
Blepharospasm/eyelid-opening
apraxia
1 (2)
0
1 (2)
0
0
atients with GPi
DBS
STN DBS group there
in L-dopa
Drooling
0 was no difference
1 (2)
1 (2) equiv- 0
0
alent doses between
characteristics and
clinical values of the
Orthostatism
0 patients 0with and without
1 (2) AEs. 0
0
vision between the
1 (2) difference 0in disease 0
0
However, there was0 a significant
aseline, the onlyDouble
difference
Pain
0
2 (4)
0
0
0
duration between the0 STN DBS1 (2)
patients with0AEs (16.9 0
in the severity
of dyskinesias: those
Paresis
0
Bone fracture
0
0
2 (4)
0
0
419
Severe
No. (%)
0
0
0
1 (5)
0
0
0
1 (5)
1 (5)
0
1 (5)
0
0
1 (5)
0
0
0
0
0
0
l. 23, No. 3, 2008
years) as compared with those without AEs (14.1 year;
P 0.042). Also, the percentage of improvement “onstimulation on-medication” in UPDRS III (motor) of
STN DBS patients with AEs was lower than in those
without AEs (P 0.037).
2. Most AEs affected patients’ cognitive and pyschiatric
status, speech, postural stability, and gait.
3. AEs occurred in a greater proportion of patients who
had STN DBS than those who had GPi DBS.
4. In the STN DBS group, patients with AEs had a
29
振戦優位型パーキンソン症候群:臨床像と LRRK2 遺伝子変
異スクリーニング
Tremor Dominant Parkinsonism: Clinical Description and LRRK2 Mutation Screening
*
Jordi Clarimón, PhD, Javier Pagonabarraga, MD, Coro Paisán-Ruíz, PhD, Antonia Campolongo, BSc, Berta Pascual-Sedano, MD, PhD, JoséFélix Martí-Massó, MD, PhD, Andrew B. Singleton, PhD, and Jaime Kulisevsky, MD, PhD
*
Memory Unit, Alzheimer’s Laboratory, and Centro de Investigación Biomédica en Red (CIBERNED), Neurology Department, Sant Pau Hospital,
Barcelona, Spain
振戦優位型パーキンソン症候群(tremor dominant
が全患者に最も強い苦痛および運動障害をもたらしてい
parkinsonism; TDP)の特徴として,安静時および動作
たが,一方,患者の大半では固縮および/または動作緩
時振戦が初期から顕著であること,パーキンソン徴候が
慢は臨床的に問題となることはなかった。また,本研究
軽度であること,薬物療法への反応性が予測できないこ
では全患者において,leucine-rich repeat kinase 2
と,特発性パーキンソン病(idiopathic Parkinson’
s
(LRRK2 )遺伝子の全コーディング領域をシークエンシ
disease; PD)よりも予後が良好であることが挙げられ
ングした。解析の結果,新規に検出された Val2390Met
る。本研究では,TDP 患者 26 例の臨床像と長期経過
変異は,他の 864 の染色体には認められなかった。今
を報告する。平均罹病期間は 6.5 ± 3 年であり,患者
回の結果から,LRRK2 変異に伴う臨床像は多彩である
の 61.5%に振戦の家族歴が認められ,73%は薬物療法
ことが示唆された。また,TDP は PD スペクトル内に
を 必 要 と し な か っ た。 ま た, 患 者 の 65.4 % で は
含まれる 1 つのサブタイプであり,主な特徴として,運
123
I-Ioflupane SPECT で線条体のトレーサ取り込みが
動障害を伴う振戦を除けばパーキンソン徴候が軽度で
低下しており,嗅覚識別検査では検査した全例(22 例)
あること,および予後が良好であることが挙げられる。
で異常が認められた。動作時および安静時振戦の合併
Movement Disorders Vol. 23, No. 4, 2008, pp. 518-523
Key Word 振戦優位型パーキンソン症候群,パーキンソン,振戦,LRRK2
30
520
Abstract
J. CLARIMÓN ET AL.
TABLE 1. Demographic and clinical characteristics of the patients.
Patient
N/Gender
Age at
onset
Family
history
1/F
2/M
3/F
4/F
5/F
6/F
7/F
8/M
9/F
10/F
11/M
12/F
13/F
14/M
15/M
16/F
17/F
18/M
19/F
20/F
21/F
22/M
23/F
24/M
25/M
26/M
72
54
73
61
65
61
67
57
72
58
75
75
72
58
65
60
68
74
73
77
70
66
65
63
52
83
No
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
Yes
No
Yes
No
No
Yes
Yes
No
No
Yes
No
Yes
Yes
No
Yes
Yes
Initial
symptoms*
ATT
ATT
ATT
ATT RTT
ATT
ATT
ATT RTT
ATT
ATT RTT
ATT
ATT RTT
ATT RTT
ATT
ATT RTT
ATT
ATT RTT
ATT
ATTRTT
ATTRTT
ATT
ATT
ATT RTT
ATT
ATT RTT
ATT RTT
ATT
Time
to1st
visit
(yr)
Follow
up (yr)
Clinical
examination**
UPDRS-III 1st
visit Tot/TS/
PIGD (Rt)
UPDRS-III
Last visit Tot/
TS/PIGD (Rt)
DAT***
5
5
2
2
7
4
1
10
5
6
3
2
5
2
2
7
5
1
3
2
1
1
10
1
1
3
6
7
3
6
10
6
6
14
10
11
5
3
7
3
4
6
7
3
6
4
2
7
13
9
6
5
RT,AT,R
RT,AT,R,B
RT,AT
RT,AT
RT,AT,R,B
RT,AT
RT,AT
RT,AT,R
RT,AT,B
RT,AT,R,B
RT,AT,R,B
RT,AT,R
RT,AT
RT,AT
RT,AT,R,B
RT,AT,R,B
RT,AT,R
RT,AT,B
RT,AT,B
RT,AT,B
RT,AT,R,B
RT,AT,R,B
RT,AT,B
RT,AT,R,B
RT,AT,R,B
RT,AT
7/6/0 (1.5)
5/5/0 (1.5)
3/3/0 (1.5)
6/4/0 (1.5)
4/4/0 (1.5)
6/6/0 (1.5)
4/4/0 (1.5)
4/4/0 (1.5)
8/8/0 (1.5)
5/5/0 (1.5)
7/7/0 (1.5)
8/7/1 (1.5)
2/2/0 (1.5)
5/5/0 (1.5)
4/4/0 (1.5)
5/5/0 (1.5)
3/3/0 (1.5)
7/7/0 (1.5)
4/4/0 (1.5)
3/3/0 (1.5)
4/4/0 (1.5)
7/7/0 (1.5)
5/5/0 (1.5)
5/5/0 (1.5)
6/6/0 (1.5)
3/3/0 (1.5)
10/8/0 (1.5)
18/6/1 (1.5)
5/5/0 (1.5)
10/6/0 (1.5)
20/7/2 (1.5)
12/9/0 (1.5)
6/6/0 (1.5)
9/7/1 (1.5)
19/8/2 (1.5)
18/8/2 (1.5)
14/8/1 (1.5)
18/7/2 (1.5)
4/4/0 (1.5)
10/7/0 (1.5)
16/8/1 (1.5)
18/9/2 (1.5)
13/7/1 (1.5)
12/7/2 (1.5)
7/7/0 (1.5)
8/7/1 (1.5)
9/6/1 (1.5)
18/9/2 (1.5)
17/8/1 (1.5)
8/5/0 (1.5)
14/8/1 (1.5)
9/9/0 (1.5)
N
A
N
N
A
N
N
A
A
A
N
A
N
A
A
/A
A
N
N
A
A
A
A
A
A
A
Hyposmia
Yes
Yes
NA
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
NA
Yes
Yes
NA
Yes
NA
Yes
Yes
Yes
Yes
*Initial symptoms were referred by the patients. ATT: action-type tremor; RTT: resting-type tremor.
**Clinical examination refers to the last visit. RT: resting tremor; AT: action tremor; R: rigidity; B: Bradykinesia.
***Altered (A) or not altered (N) SPECT.
UPDRS-III Tot, total UPDRS-III score; TS, tremor score (mean postural and action tremor scores of both hands and feet in UPDRS-III); PIGD, postural instability and
gait disturbances score (mean gait and postural instability scores in UPDRS III); Rt, ratio TS/PIGD.
the disease, bradykinesia appeared in fourteen patients
(53.8%) and rigidity in 14 patients (53.8%). Co-occurrence of bradykinesia and rigidity was found in 10 patients (38.5%). Combined AT and RT continued to be the
Clinical Examination at First Visit
most annoying and disabling symptom in all the patients,
At first clinical visit, combined action (AT) and RT in
whereas rigidity and/or bradykinesia were clinically irboth hands was documented in 23 patients
A (88%), and
relevant or not present in most of them. Only three
was symmetric in 12 of them (52%). Three patients
individuals presented significant bradykinesia or rigidity.
(12%) showed bilateral and asymmetric AT in both
Although treatment with levodopa (L-dopa) was initiated
hands with unilateral RT in the most affected hand.
in all the patients with up to a daily dose of 600 mg, drug
Three patients with AT and RT in both hands also
response was achieved in only three cases. Treatment
showed AT and RT in the lower limbs. Amplitude of AT
with propranolol up to a daily dose of 120 mg was
and RT was similar in 16 patients (60%), while AT was
attempted in 80% of the sample, but AT improved in
greater in six patients (24%), and tremor was greater at
only one individual. During the follow-up, 19 patients
rest in four (16%). Mild generalized bradykinesia was
(73%) did not receive any treatment. Absence of renoted in only two patients, and mild rigidity in one arm
Cys
va12390Met
sponseHis
to previous medications and mildness of sympwas observed in one patient. None of the patients showed
toms,
prompted
the patients not to use any medication.
unilateral tremor. Intentional tremor,
B when present, was
In
all
the
patients
the ratio of the tremor score (mean
less or as intense as postural tremor
in all the patients.
Homo_sapiens
postural and action tremor scores of both hands and feet
Pan_troglodytes
Rattus_norvergicus
Clinical Examination and Response
to Treatment at
Mus_musculus
in UPDRS subscale III) between the postural instability
Last VisitCanis_familiaris
Gallus_gallus
and gait difficulties (PIGD) score (mean gait and postural
Xenopus_laevis
instability scores in UPDRS III) was 1.5 in both the
The last clinical visit occurred aTetraodon
meannigroviridis
of 6.5 3 years
FIG.
1. (A)the
Electropherograms
showing
thelast
LRRK2
sefirst and
visit,exon
thus48accomplishing
suggested criteria
[range, 2–14] after symptom onset.
During
course of
RTT in the left hand. No patient was complaining of
slowness, gait disturbance, or speech problems at disease
onset.
Movement Disorders, Vol. 23, No. 4, 2008
quences flanking the c.G7168A heterozygous mutation in patient 15
(bottom) as well as a wild type genotype (top). Amino acid translations
are shown below. (B) Human Dardarin protein sequence aligned with
other orthologs.
31
パーキンソン病の発症リスクに対する喫煙・コーヒー・NSAID
の複合効果
Combined Effects of Smoking, Coffee, and NSAIDs on Parkinson’s Disease Risk
*
Karen M. Powers, BS, Denise M. Kay, PhD, Stewart A. Factor, DO, Cyrus P. Zabetian MD, MS, Donald S. Higgins, MD, Ali Samii, MD, John G.
Nutt, MD, Alida Griffith, MD, Berta Leis, PhD, John W. Roberts, MD, Erica D. Martinez, BS, Jennifer S. Montimurro, BS, Harvey Checkoway,
PhD, and Haydeh Payami, PhD
*
Department of Environmental and Occupational Health Sciences, School of Public Health and Community Medicine, University of Washington,
Seattle, Washington
パーキンソン病(Parkinson’
s disease; PD)が,喫煙・
NSAID(OTC 薬)の使用は個別因子として PD 発症リ
コーヒー摂取・非ステロイド系抗炎症薬(nonsteroidal
スクを 20 ~ 30%有意に低下させた。2 因子および 3
anti-inflammatory drug; NSAID)の各因子と逆相関関
因子の組み合わせにおいて,PD 発症リスクはそれぞれ
係にあることは個々に報告されているが,これらの複合
37 ~ 49%および 62%低下した。喫煙とコーヒー摂取
効果はこれまで検討されていない。これらの各因子ある
では,累積曝露量が増えるほど有意にリスクが低下する
いは 2 因子および 3 因子の組み合わせと PD との関連
傾向がみられ,用量反応性との相関が示唆された。3 因
性について定量するため,PD 患者 1,186 例と対照被
子すべての組み合わせを検討すると,喫煙・コーヒー摂
験者 928 例を対象に,関連解析を用いた症例対照研究
取の程度が最高レベルで NSAID 使用歴もあるとリスク
を実 施した。本 研 究は NeuroGenetics Research
が 87%低下すると推定された(OR = 0.13,95%信
Consortium において実施した。被験者は,
喫煙,
コーヒー
頼区間= 0.06 ~ 0.29)
。本知見が真の生物学的防御効
摂取,NSAID の使用に関する定型的な質問票に回答し
果を反映しているかどうかについては,今後検討する必
た。無条件ロジスティック回帰分析を用いてオッズ比
要がある。
(odds ratio; OR)を計算した。喫煙,コーヒー摂取,
Movement Disorders Vol. 23, No. 1, 2008, pp. 88-95
Key Word パーキンソン病,喫煙,コーヒー,NSAID,非ステロイド系抗炎症薬
32
of about 20% for users of OTC NSAIDs for both early
and late onset PD, but they were not statistically significant. Stratified analysis by family history revealed PD
0.06 – 0.29, Table 5C). Again, results were the same
when relatives were excluded (OR 0.13, 95% CI:
0.06 – 0.29).
Abstract
TABLE 4. Associations of Parkinson’s disease with NSAID use
Men and Women
NSAID use
OTC
Never
Evera
NSAID-yearsb
0
0–1.4
1.5–3.0
3
P for trend
Rx
Never
Evera
NSAID-yearsb
0
0–0.29
0.3–2.0
2
P for trend
OTC or Rx
Never
Evera
Men
Women
Cases
Controls
OR*
95% CI
Cases
Controls
OR*
95% CI
Cases
Controls
OR*
95% CI
483
677
310
597
1.0
0.81
Ref
0.67–0.98
334
439
153
215
1.0
0.87
Ref
0.66–1.13
149
238
157
382
1.0
0.73
Ref
0.55–0.98
543
198
190
214
359
177
193
169
1.0
0.80
0.75
0.98
Ref
0.62–1.04
0.58–0.97
0.75–1.27
0.387
374
125
122
140
173
66
68
56
1.0
0.82
0.79
1.09
Ref
0.57–1.18
0.55–1.13
0.75–1.59
0.908
169
73
68
74
186
111
125
113
1.0
0.76
0.69
0.87
Ref
0.53–1.11
0.47–1.01
0.59–1.27
0.244
782
368
572
321
1.0
0.92
Ref
0.76–1.13
542
225
255
103
1.0
0.99
Ref
0.75–1.32
240
143
317
218
1.0
0.87
Ref
0.66–1.14
805
110
108
122
590
102
88
106
1.0
0.92
0.99
0.97
Ref
0.68–1.25
0.72–1.36
0.72–1.30
0.787
560
61
67
74
260
33
27
34
1.0
0.88
1.10
0.97
Ref
0.55–1.40
0.68–1.77
0.62–1.51
0.985
245
49
41
48
330
69
61
72
1.0
0.99
0.89
0.96
Ref
0.65–1.49
0.58–1.39
0.63–1.44
0.695
408
769
256
663
1.0
0.83
Ref
0.68–1.02
289
496
131
240
1.0
0.88
Ref
0.67–1.15
119
273
125
423
1.0
0.77
Ref
0.56–1.04
*Odds ratio adjusted for smoking, coffee, age, ethnicity,and state (and gender for men and women combined)
a
Includes those who said yes to NSAIDs but did not indicate how long.
b
NSAID times/day years.
PD, SMOKING, COFFEE, AND NSAIDS
Movement Disorders, Vol. 23, No. 1, 2008
93
TABLE 5. Joint effects of smoking, coffee, and NSAIDs
Men and Women
Exposure
Cases
Controls
OR
Men
95% CI
Cases
Controls
Women
OR
95% CI
Cases
Controls
OR
95% CI
A. Two-way categorical comparisonsa
Smoking
No
Yes
No
Yes
Smoking
No
Yes
No
Yes
NSAIDs
No
Yes
No
Yes
Coffee
Low
Low
High
High
NSAIDs
No
No
Yes
Yes
Coffee
Low
Low
High
High
448
266
207
254
315
183
166
254
1.0
0.85
0.80
0.51
Ref
0.66–1.09
0.62–1.05
0.40–0.65
264
194
128
197
94
77
58
141
1.0
0.87
0.76
0.49
Ref
0.61–1.24
0.52–1.13
0.35–0.67
184
72
79
57
221
106
108
113
1.0
0.82
0.82
0.59
Ref
0.57–1.18
0.57–1.17
0.40–0.86
226
181
429
339
126
129
355
308
1.0
0.70
0.78
0.63
Ref
0.50–0.98
0.59–1.03
0.48–0.84
141
147
251
244
55
75
97
143
1.0
0.87
0.99
0.71
Ref
0.57–1.34
0.66–1.47
0.48–1.05
85
34
178
95
71
54
258
165
1.0
0.57
0.65
0.59
Ref
0.33–0.99
0.44–0.95
0.39–0.90
237
477
170
291
135
363
120
300
1.0
0.88
0.82
0.63
Ref
0.67–1.15
0.59–1.14
0.47–0.84
163
295
125
200
60
111
70
129
1.0
0.93
0.74
0.61
Ref
0.63–1.35
0.48–1.14
0.42–0.90
74
182
45
91
75
252
50
171
1.0
0.85
1.03
0.65
Ref
0.58–1.26
0.61–1.75
0.43–1.00
Smoking
Lowest
Middle
Highest
Coffee
No
No
No
No
Yes
Yes
Yes
Yes
Low
Low
High
High
Low
Low
High
High
No
Any
Highest
Lowest
Any
Highest
NSAIDs
Cases
B. Three-way categorical comparisonsa
No
157
Yes
291
No
69
Yes
138
No
80
Yes
186
No
101
Yes
153
C. Three-way dose trendsb
No
107
No/Yes
1057
Yes
11
Controls
OR
95% CI
83
232
43
123
52
131
77
177
1.0
0.76
0.77
0.62
0.63
0.73
0.52
0.38
Ref
0.54–1.06
0.47–1.25
0.43–0.91
0.39–0.99
0.50–1.05
0.34–0.78
0.27–0.55
63
822
33
1.0
0.74
0.13
Ref
0.53–1.04
0.06–0.29
P for trend 0.001.
ORs were adjusted for age, ethnicity, and state; and for gender for men and women combined; and mutually adjusted for smoking, NSAIDs and
coffee as appropriate
a
Categories were defined as ever or never smoker (Yes, No), below or above median (60 cups/day yrs ) consumption of coffee (low, high); and
ever or never use of OTC or Rx NSAID (Yes, No).
b
For dose trends, the lowest dose group included subjects who did not smoke and drank the least coffee (lowest quartile of 14 cups/day yrs)
and never used NSAIDs. The highest dose group included subjects who smoked the heaviest (highest quartile of 40 pack-years), drank the most
coffee (highest quartile of 120 cups/day yrs) and used OTC or Rx NSAIDs (small sample size prevented using highest dose for NSAIDs). The
middle group included all other subjects who did not qualify for the lowest or the highest strata.
DISCUSSION
Although smoking, coffee, and NSAIDs have been
extensively studied individually, to our knowledge,
30% for individual effects to 37% to 49% for two-way
joint effects, and to 62% for three-way combination.
Considering dosage of coffee and smoking, risk was
reduced by 87% in individuals who smoked the most
33
パーキンソン病患者の主訴としての非運動症状:臨床病理学的
研究
Nonmotor Symptoms as Presenting Complaints in Parkinson’s Disease: A Clinicopathological Study
*
Sean S. O’Sullivan, MRCPI, David R. Williams, PhD, David A. Gallagher, MRCP, Luke A. Massey, MRCP, Laura Silveira-Moriyama, MD, and
Andrew J. Lees, FRCP
*
Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, London, United Kingdom
非運動症状(nonmotor symptoms; NMS)は,パーキ
NMS を主訴とする場合,PD の診断が遅れる傾向にあ
ンソン病(Parkinson’
s disease; PD)後期における病
。NMS を主
る(Mann-Whitney U 検定,p = 0.001)
悩の主要原因として認知されつつある。また,PD の前
訴とする患者は,初診時に誤診される可能性が高く,神
駆期における NMS も,一部の患者の臨床像を構成する
経内科医よりも整形外科医やリウマチ科医に紹介される
要素としてよく知られているが,病理学的に証明された
ことが多かった(神経内科医に紹介される頻度:NMS
PD 症例における主訴としての NMS の有病率,ならび
を主訴とする患者群 5.5%,運動症状を主訴とする患者
に NMS が臨床管理に及ぼす影響については明らかでな
。病理学的に
群 44.2%,カイ二乗検定 p < 0.0001)
い。 本 研 究 で は,Queen Square Brain Bank for
確認された PD 患者において,NMS は主訴として一般
Neurological Diseases に登録され,病理学的に証明さ
的であるが,初診時の誤診により,潜在的に不適切な医
れた PD 症例 433 例の主訴を,臨床症例記録から特定
学的介入が行われている可能性がある。主訴としての
した。PD 患者 433 例中 91 例(21%)が NMS を主
NMS は,運動に対する薬物療法の効果には影響を及ぼ
訴とし,
NMS で最も高頻度にみられたのは疼痛(15%)
,
さないが,短い罹病期間と関係している(カイ二乗検定
排尿障害(3.9%)
,
不安または抑うつ(2.5%)であった。
p = 0.016)
。
Movement Disorders Vol. 23, No. 1, 2008, pp. 101-106
NMS AS PRESENTING COMPLAINTS IN PD
103
Key Word パーキンソン病,非運動性,疼痛,抑うつ,自律神経性
TABLE 1. Patient characteristics and presenting symptoms
Male:female (%)
Number of patients with a documented family history
of PD (%)
Age of PD onset mean SD
Interval between symptom onset and diagnosis of
PD; median, interquartile range (years)
Duration of PD before death; mean SD (years)
Age of death; mean SD
First symptoms including tremor
First symptoms including bradykinesia
First symptoms including rigidity
First symptoms including unspecified gait disturbance
First symptoms including pain
First symptoms including urinary dysfunction
First symptoms including depression or anxiety
Other symptoms
Total cases
(N 433)
Cases with “motor
symptoms” at
presentation
(N 342)
Cases without “motor
symptoms” at
presentation
(N 91)
P value
274:159 (63:37%)
31 (7%)
215:127 (63:37%)
28 (8.2%)
59:32 (65:35%)
3 (3.3%)
NSa
0.08a
60.9 10.4 years
1.1 (0.9–2.4)
60.6 10.6 years
1.0 (0.8–2.2)
61.9 9.5 years
1.6 (1.0–3.0)
NSb
0.001c
14.9 6.9
75.8 7.4
196 (45.3%)
136 (31.4%)
44 (10.2%)
51 (11.8%)
65 (15%)
17 (3.9%)
11 (2.5%)
59 (13.6%)
15.3 7.0
75.9 7.6
196 (57.3%)
136 (39.8%)
44 (12.9%)
51 (14.9%)
17 (5%)
2 (0.6%)
0
34 (9.9%)
13.4 6.6
75.3 6.6
0
0
0
0
48 (52.7%)
15 (16.5%)
11 (12.1%)
25 (27.5%)
0.016b
NSb
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
a 2
.
Student’s t-test.
c
Mann-Whitney U.
b
34
A small percentage of patients from the nonmotor
group (4.4%) had no bradykinesia, rigidity, or tremor
documented 2 years after symptom onset. After the same
disease history. There was no difference in the mean
latency from first symptom onset to the development of
hallucinations between groups (motor group 131 75
PATHOLOGY OF ESSENTIAL TREMOR
In a follow-up study, data on 10 ET and 12 control
本態性振戦に伴う神経病理学的変化の新知見
brains were presented. Four ET brains (including one
41
previously reported)
40
had a similar pattern of restricted
The Emerging Neuropathology
of Essential Tremor
Lewy body involvement (see Fig. 1). Four other cases
exhibited cerebellar degenerative changes. First, the
number of torpedoes was increased 10-fold compared to
*
GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA
similarly-aged control brains (see Fig. 2) and, second,
**
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
***
there Disease
was anand
increase
the number
Bergmann
glial Columbia University, New York,
Taub Institute for Research on Alzheimer’s
the AginginBrain,
College of of
Physicians
and Surgeons,
New York, USA
cells in these cases. Purkinje cell loss was similar in
****
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
cases and controls, although this was not rigorously
quantified. Based on these initial results, the ET cases
formed two pathological subtypes: those with restricted
LC Lewy bodies (referred to as the “Lewy body variant
of ET” or LBVET) and those without such Lewy bodies
本態性振戦(essential tremor; ET)は最もよくみられ
みられる基礎的な脳変化の一部が明らかになりつつあ
but with cerebellar degenerative changes (referred to as
る神経障害の 1 つであるが,それと同時に最も理解の
る。この種の研究は ET の病態生理の理解を進展させる
“cerebellar ET”).
In theの基礎にある病理
same year, an eleventh
ET case was reported
進んでいない神経疾患でもある。ET
とともに,この広くみられる運動障害の治療法開発に道
separately.42 The patient was 90-years-old, with a 30
解剖学については,最近まで理解の手掛かりさえつかめ
を開くものと考えられる。
year history of ET. On postmortem examination, there
ていなかったが,現在では剖検研究により,ET
was segmental loss患者に
of Purkinje cells and an increased
FIG. 2. Cerebellar tissue from several ET cases
number of torpedoes and Bergmann glial cells. In addidoes in close proximity (top, LH and E 200 ma
left, LH and E 400 magnification), and one to
tion, there were extensive changes in the dentate nucleus:
Bielschowsky-stained,
magnification). (Perm
Movement
Disorders
Vol.
23,
No. 2, 2008, pp.400
174-182
neuronal atrophy, neuronal loss, microglial clusters, and
as follows: Figure 2, top: Archives of Neurology
a reduction in efferent fibers (i.e., myelin loss involving
page 1191, Copyright © 2006, American Medic
Key Word 本態性振戦,病理学,小脳,レビー小体,神経変性
rights reserved. Figure 2, bottom left: Louis et
the hilum). That case,42 with more marked cerebellar
findings in essential tremor. Neurology, 2006;66:1
41
degeneration than in those previously-reported, further
extended the range of pathological changes observed in
cerebellar ET.
Because Purkinje cell loss was not
literature,30-33 and because segmental l
cells was observed in ETCBR cases,42 t
gators undertook a more rigorous quan
Purkinje cell linear density, using calbin
tochemistry in ET cases and control
study,43 of 14 ETCBR ET cases and 11 c
cell linear density differed by diagnosis:
1.27 cells/mm), LBVET (3.33 1.06
cerebellar ET (2.14 0.82 cells/mm), P
main difference being between cerebell
controls, where the reduction in Pur
38.2% (P 0.04) (see Fig. 3).43 Low
linear density was also associated with
of torpedoes (r 0.42, P 0.04),
FIG. 1. Two LBVET cases. Two panels on left are Hematoxylin and
Eosin (H&E) or Luxol Fast Blue and H&E (LH&E) stained sections of
torpedoes and Purkinje cell loss may
the LC in a first ET case (top, 400) and a second ET case (bottom,
features of cerebellar degeneration in th
200) showing multiple Lewy bodies (arrows). The top right panel
At present, data are available for
(200) shows an alpha-synuclein-stained section of numerous Lewy
bodies in the LC of one of these ET cases. The bottom right panel is an
brains. Three-quarters of these exhib
alpha-synuclein-stained section of the substantia nigra pars compacta
changes of the cerebellar variant of ET w
(100) showing normal pigmentation and cellularity, and complete
have LBVET. Of additional note is th
absence of Lewy bodies or Lewy neurites in one of these ET cases.
(Permissions for Figure 1 as follows: Figure 1, top left and top right:
detectable changes in the inferior oliva
Archives of Neurology, 2005, volume 62, page 1006, Copyright ©
nucleus, thalamus, caudate, putamen, glo
2005, American Medical Association. All rights reserved. Figure 1,
motor cortex in these brains. Among tho
bottom left and bottom right: Louis et al. Neuropathologic findings in
essential tremor. Neurology, 2006;66:1756 –1759.)
lar ET, besides the degenerative cerebell
*, **, ***, ****
Elan D. Louis, MD, MSc, and Jean Paul G. Vonsattel, MD
Movement Disorder
35
淡蒼球の深部脳刺激により分節性および全身性ジストニア患者
の生活の質が改善される:模擬刺激を対照群とした前向き無作
為試験の結果
Pallidal Deep Brain Stimulation Improves Quality of Life in Segmental and Generalized Dystonia:
Results from a Prospective, Randomized Sham-Controlled Trial
Joerg Mueller, MD, Inger M. Skogseid, MD, Reiner Benecke, MD, Andreas Kupsch, MD, Thomas Trottenberg, MD, Werner Poewe, MD, Gerd H.
Schneider, MD, Wilhelm Eisner, MD, Alexander Wolters, MD, J.U. Müller, MD, Günther Deuschl, MD, Marcus O. Pinsker, MD, Geir K. Roeste,
MD, Juliane Vollmer-Haase, MD, Angela Brentrup, MD, Martin Krause, MD, Volker Tronnier, MD, Alfons Schnitzler, MD, Jüergen Voges, MD,
Guido Nikkhah MD, PhD, Jan Vesper, MD, Markus Naumann, MD, and Jens Volkmann, MD, for the Deep-Brain Stimulation for Dystonia Study
Group
本研究では,一次性の分節性ジストニアと全身性ジスト
HRQoL が有意に改善した。オープンラベルの延長試験
ニアにおける深部脳刺激(deep brain stimulation;
では,6 ヵ月間の神経刺激後,SF-36 のすべての領域
DBS)と模擬刺激を比較した最初の無作為対照試験の
で有意な改善が認められた。以上の結果から,DBS は
一環として,健康関連の生活の質(health-related
一次性ジストニア患者の HRQoL に好影響を与えること
quality of life; HRQoL)を SF-36 で評価した。模擬刺
が示された。
激を対照群とする 3 ヵ月間の試験後,実刺激群のみで
Movement Disorders Vol. 23, No. 1, 2008, pp. 131-134
Key Word ジストニア,深部脳刺激,淡蒼球内節,生活の質
0
PF
SF
RP
RE
MH
VT
BP
GH
z-score
95
-2
-3
-4
baseline
3 months (sham-stimulation)
3 months (neurostimulation)
6 months
99
0
Percentiles of German normal population
75
-1
36
50
FIG. 1. SF-36 domain scores of individual patients were z-transformed and related to the percentile level of the agematched German normal population.
Differences are considered relevant if
they exceed one SD (z
1). PF, physical function; SF, social function; RP,
role limitations due to physical problems;
RE, role limitations due to emotional
problems; MH, mental health; VT, vitality; BP, bodily pain; GH, general
health.*P 0.05, **P 0.01.
ボツリヌス毒素治療未経験の頸部ジストニア患者における A
型ボツリヌス毒素と B 型ボツリヌス毒素の比較:無作為二重
盲検非劣性試験
Botulinum Toxin Type B vs. Type A in Toxin-Naïve Patients with Cervical Dystonia: Randomized,
Double-Blind, Noninferiority Trial
*, **
Eric J. Pappert, MD, and Terry Germanson, PhD, for The Myobloc/Neurobloc European Cervical Dystonia Study Group
*
Solstice Neurosciences, Inc, Malvern, Pennsylvania, USA
**
University of Texas Health Science Center, San Antonio, Texas, USA
本研究の目的は,ボツリヌス毒素(botulinum toxin;
る BoNT-B の非劣性試験としてデザインし,患者 111
BoNT) 治 療 未 経 験 の 頸 部 ジ ス ト ニ ア(cervical
例を無作為に BoNT-A 群(55 例)と BoNT-B 群(56 例)
dystonia; CD)患者において,A 型ボツリヌス毒素
に割り付けた。注射 4 週間後の TWSTRS 総合スコアの
(botulinum toxin type A; BoNT-A)と B 型ボツリヌス
改善度は,BoNT-A 群に比べ BoNT-B 群は劣っていな
毒素(botulinum toxin type B; BoNT-B)の有効性,安
かった〔補正後の平均値:BoNT-A 群 8.8(SE 1.2)
,
全性,効果持続期間を比較することである。BoNT 治療
BoNT-B 群 11.0(SE 1.2)
,per-protocol 集団(per-
未経験の CD 患者を BoNT-A 群または BoNT-B 群に無
protocol-population; PPP)
〕
。効果持続期間の中央値は
作為に割り付けて治療を 1 回行い,ベースライン時お
BoNT-A 群 と BoNT-B 群 と の 間 に 差 が な か っ た
よび注射後 4 週間ごとに二重盲検評価を実施した。主
(BoNT-A 群:13.1 週,BoNT-B 群 13.7 週,p = 0.833,
要評価項目は,ベースライン時と BoNT 注射 4 週間後
PPP)
。注射部位の疼痛および嚥下障害の発生率に有意
を比較した Toronto Western Spasmodic Torticollis
差はなかった。軽度の口内乾燥の発生率は BoNT-B 群
Rating Scale(TWSTRS)のスコアの変化とした。副次
で高かったが,中等度/重度の口内乾燥に両群間で差は
的評価項目は,TWSTRS サブスケールのスコアの変化,
認められなかった。本研究の結果,BoNT-A と BoNT-B
疼痛,医師および患者による治療効果の総合的印象,効
はいずれも BoNT 治療未経験の CD 患者の治療に有効
果持続期間,安全性とした。本試験は BoNT-A に対す
かつ安全であることが示された。
Movement Disorders Vol. 23, No. 4, 2008, pp. 510-517
Key Word A 型ボツリヌス毒素,B 型ボツリヌス毒素,頸部ジストニア,ボツリヌス毒素治療未経験
1.0
Type A (Medium Survival=13.1 week)
Type B (Medium Survival=13.7 week)
Probability of <=80% Loss of Benefit
0.9
0.8
FIG. 2. Kaplan-Meier curves for the
time from the assessment to the first TWSTRS-total score demonstrating a 80%
loss in the improvement attained. Time 0
is the time of injection. Subjects who do
not show improvement in the TWSTRStotal score at week 4 after the initial
injection are considered to lose benefit at
week 4.
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Hazard Ratio (95%IC):0.95 (0.56,1.59)
0.0
Week
0
1
2
Type A (N)
Type B (N)
3
4
5
6
7
8
9
10
11
12
13
40
43
40
43
40
43
40
43
40
43
38
40
37
39
36
38
33
29
20
17
14
14
12
15
16
17
18
19
20
21
22
14
9
13
9
10
8
6
7
6
5
5
5
4
4
3
3
37
594
SCHNEIDER AND BHATIA
Woodhouse Sakati 症候群におけるジストニア:新たに同定
sory neuropathy, mental retardation, alopecia, hypogonadism, and diabetes mellitus. The autosomal recessive
された 1 家系の報告と文献レビュー
inheritance and the syndromic presentation were suggesof Woodhouse
Sakati syndrome,
Dystonia in the Woodhouse Sakati Syndrome: A New tive
Family
and Literature
Review matching previous
reports. A diagnosis of mitochondrial disease was considered but excluded by muscle biopsy and mitochonSusanne A. Schneider, MD and Kailash P. Bhatia, MD
drial mutations were negative. Other causes of secondary
*
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, United Kingdom
dystonia were also excluded by appropriate tests.
Woodhouse Sakati syndrome is a rare autosomal recessive disorder. To date about 25 families1–12 have been
described (Table 1), mostly from the Middle East (Saudi
Arabia, Jordan, Lebanon, Turkey), where consanguinity
FIG. 2. MRI of our index case demonstrates multiple white matter
is not uncommon. Our patients were from a consanguinfoci with confluent lesions.
Woodhouse Sakati 症候群は,稀な常染色体劣性神経
候群の報告例の多くは中東諸国出身の家系であるが,白
eous family and from that region. Only two families from
内分泌疾患であり,脱毛,性腺機能低下症,糖尿病,精
人の症例も稀に報告されている。本論文では,新たに同
Caucasian descent have been reported.10,12
VDRL,
TPHA, HIV antibodies, HBV antibodies, voltA literature 1
review
revealed that neurological
features
age-gated
potassium channel
antibodies. Genetic testing
神遅滞,感音性難聴,
錐体外路徴候の合併を特徴とする。
定された中東の
家系の患者(同胞)2
例の臨床像を
include extrapyramidal signs, dysarthria and dysphagia,
revealed
a
normal
karyotype.
DYT1
gene
and
DM
(Myo同症候群に伴う運動障害は,主に思春期発症型の四肢
詳述し,本疾患について運動障害専門医の注意を喚起し
cognitive decline, deafness, seizures, and polyneuropathy.
tonic dystrophy) gene mutations were excluded. An ECG
のジストニアと舞踏病である。通常,顔面筋に障害はな
たい。また,特に神経症状ならびに運動障害に注目して
Movements were characterized by a combination of
was
normal.
dystonia and chorea with onset in adolescence or adultいが,構音障害はよく認められる。錐体路徴候と末梢神
既報告症例の所見を要約する。
Trials of levodopa, trihexyphenidyl, tetrabenazine, or
hood with focal limb onset, but spread of symptoms was
botulinum
toxin injections were not beneficial. Sakati
The com経異常の発現に一貫性はない。Woodhouse
症
common causing gait difficulties and later immobility.
bination of baclofen and clonazepam produced mild
Severe dystonic scoliosis can occur. One patient had
benefit.
cogwheel
rigidity in the absence of dystonia and chorea.1
Movement Disorders Vol. 23, No. 4, 2008, pp. 592-596
Case 2
Overall, involuntary movements were present in half of
all cases. Others may have been too young at time of
His
sister
was
similarly
affected
by
alopecia,
hypogoKey Word Woodhouse Sakati 症候群,ジストニア,性腺機能低下症,脱毛,難聴,糖尿病,精神遅滞
description to exhibit a movement disorder. Dysarthria
nadismus with primary amenorrhea, deafness, mental
may be combined with a high-pitched voice. Eye moveretardation, diabetes mellitus, and dystonia. She had additional seizures since age 2.
On examination cognitive impairment was more seTABLE 1. Summary of clinical characteristics from
vere compared to her brother with disorientation in place
previously reported cases with Woodhouse Sakati syndrome*
and time. She was emotionally
labile with a tendency to
1 cousins
laughing easily. Facial appearances and dysarthria were
● Fifty-five cases from 23 families in 12 case reports between 1973
and 2007
similar to her brother. There was hypertelorism with
● Countries of origin were mainly in the Middle East including
keratoconus. She had a female phenotype but poor secSaudi Arabia
ondary sexual development. Her height was 1.62 m, and
● Autoimmune disorder
1 cousins
Alopecia: 100%
her weight was 61 kg. She had dystonic posturing of all
Hypogonadism: 98%
four limbs with hypertrophy of her calf muscles first
Thyroid dysfunction: 30% (13/44)
noted at age 22. Limb strength and reflexes were normal
Diabetes mellitus: 60% (28/47)
● Neurological features
except for diminished knee and ankle reflexes. Plantars
Cognitive impairment/mental retardation: 75% (39/52)
were flexor. Muscle wasting was absent. Her gait was
Deafness: 74% (31/42)
wide-based and clumsy.
Extrapyramidal features (primarily chorea and dystonia): 50%
(23/47)
FSH levels were high; 17-beta estradiol levels were
Dysarthria or speech changes
low suggesting primary ovarian failure. Karyotype analSeizures
ysis was normal. Like her brother she had raised CK, and
Other rare neurological features: pyramidal signs, polyneuropathy,
Woodhouse Sakati syndrome, clinically examined
incontinence
elevated
HbA1c. An EEG showed interictal generalized/
Affected by history (deafness)
● Other features
bifrontal
epileptiform activity. Nerve conduction studies
ECG changes (T-wave abnormalities)
Affected by history (diabetes mellitus)
were
normal.
Keratoconus
*
st
st
Affected by history (mental retardation)
DISCUSSION
FIG. 1. Pedigree of patients.
The arrows indicate the here presented
cases. Filled symbols indicate examined affected individuals. By hisWe have described a sib-pair with adult-onset dystonia
tory (not examined) partially affected relatives (see key) are shown as
associated
sensory relatives
neural asdeafness,
seizures, senshaded
symbolswith
and unaffected
empty symbols.
Movement Disorders, Vol. 23, No. 4, 2008
38
Camptodactyly
Acanthosis nigrans
*Absolute numbers are given in brackets when information was not
available for all cases (for detailed work-up, see Supplementary Table).
パーキンソン病患者の抑うつ症候群に関する検証試験
A Validation Study of Depressive Syndromes in Parkinson’s Disease
*, **
Sergio E. Starkstein, MD, PhD, Marcelo Merello, MD, PhD, Ricardo Jorge, MD, Simone Brockman, MA, David Bruce, MD, Gustavo Petracca, MD, and Robert G. Robinson, MD
*
School of Psychiatry and Clinical Neurosciences, University of Western Australia, Western Australia, Australia
Department of Psychiatry, Fremantle Hospital, Western Australia, Australia
**
パーキンソン病(Parkinson’
s disease; PD)患者の大う
退,自尊心の低下,集中力低下,絶望感といった症状は,
つ病(major depression)
,小うつ病(minor depression)
,
すべて気分変調性障害に関する DSM-IV 基準の「悲哀気
気分変調性障害(dysthymic disorder)
,亜症候群性うつ
分(sad mood)
」陽性と有意に関連していた。今回のサ
病(subsyndromal depression)の診断において,PD 患
ンプ ル の 30 %は 大うつ 病,20 %は 気 分 変 調 性 障 害,
者の抑うつ症状を指標とする妥当性とその感度および特
10%は小うつ病の DSM-IV 診断基準を満たし,8%は亜
異度を検討した。ある Movement Disorders Clinic を受
症候群性うつ病の臨床基準を満たしていた。大うつ病また
診した連続した PD 患者 173 例を対象に,包括的な精神
は小うつ病の患者は,気分変調性障害患者もしくはうつ病
医学的および神経学的評価を実施した。
興味/喜びの喪失,
を伴わない患者に比べ,日常生活動作の障害,認知障害,
食欲または体重の変化,睡眠の変化,気力減退,無価値感
パーキンソン症候群の重症度が有意に高かった。本研究
または不適切な罪責感,精神運動遅滞/興奮,集中力低下,
の結果,大うつ病および気分変調性障害に関する DSM-IV
自殺念慮といった症状は,すべて大うつ病に関する DSM-
診断基準を PD 患者に適用する妥当性が示された。小うつ
IV 基準の「抑うつ気分(depressed mood)
」陽性と有意
病および亜症候群性うつ病のカテゴリーについては妥当性
に関連していた。また,食欲の変化,睡眠の変化,気力減
をさらに検証する必要がある。
Movement Disorders Vol. 23, No. 4, 2008, pp. 538-546
540
S.E. STARKSTEIN ET AL.
Key Word パーキンソン病,うつ病,気分変調,不安
TABLE 1. DSM-IV criteria for major depression and dysthymic disorder for patients with Parkinson’s disease
Hoehn–Yahr I–II
Number of patients
Major depressiona
Loss of interest/pleasure
Changes in appetite/
weight
Sleep changes
Psychomotor changes
Loss of energy
Worthlessness/guilt
Concentration deficits
Suicide ideation
Dysthymic disorderb
Number of patients
Changes in appetite
Sleep changes
Low energy
Low self-esteem
Poor concentration
Hopelessness
Additional symptomsc
Psychological anxiety
Autonomic anxiety
Hoehn–Yahr III
Hoehn–Yahr IV–V
No sad mood
Sad mood
No sad mood
Sad mood
No sad mood
Sad mood
40
40
29
34
9
21
1.3 (0.6)
2.5 (0.7)
1.6 (0.8)
2.5 (0.6)
1.6 (1.0)
2.3 (0.8)
1.1 (0.4)
1.3 (0.7)
1.3 (0.6)
1.3 (0.6)
1.0 (0.2)
1.2 (0.5)
1.1 (0.5)
1.8 (0.8)
2.0 (0.9)
2.0 (0.8)
2.3 (0.7)
2.0 (0.8)
2.3 (0.8)
1.5 (0.8)
1.0 (0.3)
1.3 (0.7)
1.4 (0.7)
1.4 (0.7)
1.1 (0.5)
1.5 (0.9)
1.0 (0.3)
1.7 (0.9)
1.7 (0.8)
2.1 (0.9)
2.4 (0.7)
1.7 (0.8)
2.4 (0.8)
1.7 (0.9)
1.3 (0.7)
1.3 (0.7)
1.6 (1.0)
1.4 (0.7)
1.2 (0.4)
1.4 (0.7)
1.2 (0.4)
1.6 (0.8)
1.8 (1.0)
2.1 (0.9)
2.2 (0.8)
1.9 (1.0)
2.4 (0.8)
1.6 (1.0)
39
1.1 (0.4)
1.4 (0.6)
1.4 (0.6)
1.1 (0.4)
1.3 (0.6)
1.1 (0.3)
21
1.5 (0.8)
1.8 (0.9)
2.4 (0.8)
1.7 (0.9)
2.2 (0.8)
2.4 (0.7)
31
1.1 (0.3)
1.3 (0.6)
1.3 (0.7)
1.0 (0.3)
1.6 (0.8)
1.0 (0.2)
12
1.8 (1.0)
1.7 (0.9)
2.3 (0.8)
1.7 (0.9)
2.0 (0.8)
1.7 (0.9)
13
1.3 (0.5)
1.0 (0.5)
1.4 (0.4)
1.2 (0.2)
1.3 (0.5)
1.0 (0.2)
5
1.8 (1.0)
2.4 (0.9)
2.8 (0.3)
2.2 (1.0)
2.2 (0.9)
2.4 (0.7)
0.6 (0.7)
0.5 (0.6)
1.3 (0.9)
1.2 (0.8)
0.4 (0.7)
0.4 (0.6)
1.2 (0.8)
1.3 (0.8)
0.5 (0.8)
0.3 (0.7)
1.0 (0.9)
1.1 (1.0)
Numbers are means (SD).
a
Effect for depressed mood: Wilks’ Lambda 0.59, df 8,160, P 0 .0001. Post hoc comparisons between patients with versus those without
sad mood showed significant differences (P 0.0001) for all individual items.
b
Effect for sad mood: Wilks’ Lambda 0.43, df 6,110, P 0.0001. Post hoc comparisons between patients with versus those without sad mood
showed significant differences (P 0.001) for all individual items.
c
Effect for depressed mood: Wilks’ Lambda 0.80, df 2,166, P 0.0001.
analyzed with a stepwise regression analysis. All P values are two-tailed.
as the dependent variables. There was a significant main
effect for sad mood (Wilks’ Lambda 0.59, df 8,160,
39
パーキンソン病患者の抑うつ有病率に関する研究を対象とした
系統的レビュー
A Systematic Review of Prevalence Studies of Depression in Parkinson’s Disease
*
Jennifer S.A.M. Reijnders, MA, Uwe Ehrt, MD, Wim E.J. Weber, MD, PhD, Dag Aarsland, MD, PhD, and Albert F.G. Leentjens, MD, PhD
*
Department of Psychiatry, Maastricht University Hospital, Maastricht, The Netherlands
パーキンソン病(Parkinson’
s disease; PD)患者にお
depression)は 22%,気分変調症(dysthymia)は
けるうつ病性障害の有病率は研究によって大きく異な
13%であった。DSM の定義によるうつ病性障害の有無
り,2.7 ~ 90%超と報告されている。今回の系統的レ
にかかわらず,臨床的に有意な抑うつ症状は患者の
ビューの目的は,各研究間で異なる設定条件および診断
35%に認められた。DSM 基準を確立するために(半)
法を考慮の上,うつ病性障害の平均有病率を算出するこ
構造化面接を行った研究では,大うつ病性障害の有病
とである。PubMed 上の Medline を用い,PD 患者の抑
率は 19%であったのに対し,構造化面接を行わずに
うつに関する研究を系統的に検索した。検索の結果,計
DSM 基準を使用した研究で報告された大うつ病性障害
104 件の論文が特定され,研究の質を検討したところ,
の有病率は 7%であった。一般集団を対象とした研究で
51 件の論文が基準を満たしていた。同一データベース
は,他の設定条件の研究に比べ,大うつ病性障害およ
を用いた公表文献が複数ある場合,重複文献はメタア
び臨床的に有意な抑うつ症状の有病率が低かった。今
ナリシスから除外した。残った 36 件の論文において
回の系統的レビューから,PD 患者における大うつ病性
PD 患 者 の 大 う つ 病 性 障 害(major depressive
障害の平均有病率は高いが,一般に考えられているほど
disorder)の加重有病率は 17%,小うつ病(minor
ではないことが示唆される。
Movement Disorders Vol. 23, No. 2, 2008, pp. 183-189
Key Word パーキンソン病,うつ病性障害,気分変調症,有病率,系統的レビュー
THE PREVALENCE OF DEPRESSION IN PD
TABLE 3. Prevalence (%) of major depressive disorder and
clinically relevant depressive symptoms in different settings
Major depressive
disorder
Population
General population
General practice
Outpatient setting
Inpatient setting
Nursing home
40
Clinically relevant
depressive symptoms
Number of
Number of
studies
Prevalence
studies
Prevalence
4
0
11
1
0
8.1
24.0
21.7
5
2
25
3
1
10.8
42.3
40.4
54.3
32.7
The prevalence of clinically significant depressive symptoms was 35%. While dysthymia may be diagnosed in
the presence of major depressive disorder or minor depression (the concept of “double depression”), it is surprising that none of the studies have looked at both minor
depression and dysthymia at the same time.
The influence of setting on the prevalence of depres-
DISCUSSION
This is the first extensive review of th
depressive disorders in Parkinson’s disea
different settings and diagnostic approac
ous studies into account. It shows that th
alence of major depressive disorder in PD
is substantial, but less than the prevalen
usually quoted. Minor depression was
and dysthymia in 13% of PD patients. I
the general population these numbers a
they are higher in hospital outpatient an
tings. We could not confirm that the prev
depression is lower when structured inte
as opposed unstructured clinical interv
diagnostic criteria, as is reported by o
review, the use of structured interviews
prevalence rates.
Two earlier reviews on the prevalence
PD have been published. Both were
extensive review that also included the
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