アルツハイマー病の血液診断法の開発に関する研究
著者
荒井 啓行
アルツハイマー病の血液診断法の開発に関する研究
(13670628)平成13年度∼平成14年度
科学研究費補助金(基盤研究(C) (2))研究成果報告書
平成15年5月
研究代表者
荒井 啓行
(東北大学医学部附属病院 助教授)
研究組織
研究代表者:荒井 啓行 (東北大学医学部附属病院 助教授)
交付決定額 (配分額)
(金額単位:千円)
直接経費 亊I ｨﾆ N 合計 平成14年度 0 ﾃ3 平成15年度 ﾃ 0 ﾃ 総計 ﾃ# 0 ﾃ#研究発表
(1)学会誌等1･ Matsui T, Morikawa Y, Tojo M, Okamura N, Maruyama M, Hirai H, Chiba H, Matsushita S, Higuchi S,生血且, Sasaki H. Cathepsin D polymorphism not
associated with AIzheimer's disease in Japanese･ Ann･ NeuroL. 49:544-545,
2001.
2･ Okamura N, △三盆且, Higuchi M, Tashiro M, Matsui T, Hu X-S, Takeda A, Itoh M, Sasaki H･ [18F】FDG-PET study in dementia with Lewy bodies and AIzheimer's disease･ Prog･ Neuro-psychopharmacol&Biol･ Psychiatry
25:447-456, 2001.
3･ Matsui T, △過し吐, Yuzuriha T, Ya° H, Miura M, Hashimoto S, Higuchi S, Matsushita S, Morikawa M, Kato A, Sasaki H･ Elevated plasma homocysteine levels and a risk for silent brain infarction in elderly people･ Stroke
32:1116-1119, 2001.
4･ Wada H, Nakajoh K, Satoh-Nakagawa T, Suzuki T, Ohrui T,生垣_且, Sasaki H.
Risk factors of asplration pneumonia in AIzheimer,s disease patients･ Geromtology 47:271-276, 2001.
5･ Matsushita S, Arai H, Yuzuriha T, Kato M, Matsui T, Urakami K, Higuchi S･
No association between DLST gene and AIzheimer's disease or Wernicke-Korsakoff syndrome. NeurobioL. Aging 22:569-574, 2001.
6･ Sekine-Aizawa Y, Hama E, Watanabe K, Tsubuki S, Kanai-Azuma M, Kanai Y,
Arai H, Aizawa H, Iwata N, Saido CT. Matrix metalloproteinase (MMP) system in brain: identification and characterization of brain-specific MMP
highly expressed in cerebellum･ Eur･ J･ Neurosci. 13:1-15, 2001.
7･ Yamagata K, Urakami K, Ikeda K, Ji Y, Adachi Y, Arai H, Sasaki H, Sato K,
Nakashima K･ High expression ofApolipoprotein E mRNA in the brains with sporadic AIzheimer's disease･ Dement･ Geriatr･ Cogn･ Disord･ 12:57162,
2001.
8･ Kimura M, Matsushita S,生血且, Takeda A, Higuchi S. No evidence of
association between a dopamine transporter gene polymorphism (1215A/G) and Parkinson's disease. Amm. Neurol. 49:276-277, 2001.
9･ Itoh N,生血且, Urakami K, Ishiguro K, Ohno H, Hampel H, Buerger K, Wil脆ng ∫, Otto M, Kretzschmar H, Moeller H-J, Imagawa M, Kohno H,
Nakashima K, Kuzuhara S, Sasaki H, and lmahori K･ Large-scale,
multi-center study ofcerebrosplnalfluid tau protein phosphorylated at serine
199 fわr the antemortem diagnosis ofAIzheimer-s disease. Ann. Neurol.
50:150-156, 2001
10･Okamura N,生垣_辻, Maruyama M, Matsui T, Tanji H, Yoshida H, Sugita M,
Sasaki H･ Serum cholesterol and cerebrospinalfluid amyloid P protein in AIzheimer's disease. I. Am. Geriat. Soc. 49:1738-1739, 2001.
1 1･Takeda M, Tanaka T, Arai H, Sasaki H, Shiji M, Okamoto K, Urakami K, Nakashima K, Matsubayashi T, Sugita M, Yoshida H･ Basic and clinical studies on the measurement ofP-amyloidlー42 in cerebrospinalfluid as a
diagnostic marker fわr AIzheimer's disease and related disorders: Multi-center
study in Japan･ Psychogeriatrics I:56-63, 200l.
12･Urakami K, Wada K,生血且, Sasaki H, Kanai M, Shoji M, Ishizu H, Kashihara K, Yamamoto M, Tsuchiya-Ikemoto K, Morimatsu M, Takashima H,
Nakagawa M, Kurokawa K, Maruyama H, Kaseda Y, Nakamura S, Hasegawa K, Oono H, Hikase C, Ikeda K, Yamagata K, Wakutani Y, Takeshima T, Nakashima K･ Diagnostic slgnificance of tau protein in cerebrosplnal nuid
from patients with corticobasal degeneration or progressive supranuclear palsy. J. Neurol. Sci. 183:95-98, 2001.
13･Nakazawa A, Usuda N, Matsui T, Hanai T, Matsushita S,虫垂主_旦, Sasaki H,
IIistochem. Cytochem. 49:187-195, 2001.
14.Maruyama M, Arai H, Sugita M, Tanji H, Higuchi M, Okamura N, Matsui T, Higuchi S, Matsushita S, Yoshida H, Sasaki H. Cerebrosplnalfluid amyloid
β1-42 in the midl cognitive impairment stage ofAIzheimer's disease. Exp.
Neurol. 172:433-436, 2001.
15･Sato E, Ohrui T, Matsui T, Arai H, Sasaki H. Folate deficiency and risk of pneumonia in older people. I. Am. Geriatr. Sol. 49:1739-1740, 2001.
16.Yamaya M, Yanai M, Ohrui T, Arai H, Sekizawa 良, Sasaki H. Antithrombotic therapy fわr prevention of pneumonia. ∫. Am. Geriatr. Soe. 49:687-688, 2001. 17･Suzuki T, Arai H, Iwasaki K, Tanji H, Higuchi M, Okamura N, Matsui T,
Maruyama M, Yabe T, Toriizuka K, Yamada H, Hanawa T, Ikarashi Y, Sasaki
H･ A Japanese herbal medicine (Kami-Untan-To) in the treatment of AIzheimer's disease: A pilot study･ AIzheimerls Rep･ 4:177-182, 2001･
18･Yamagata 良, Wakutani Y, Urakami K, Wada K, Arai H, Sasaki H, Higuchi S,
Sato K, Nakashima K･ Apolipoprotein E promotor -186G/T polymorphism and
Japanese AIzheimer's disease. AIzheimerls Rep･ 4:1611165, 2001･
19･Wakutani Y, Ito T, Wada K, Yamagata K, Adachi Y, Taniguchi M, Arai H, Sasaki H, Higuchi S, Sato K, Urakami K, Nakashima K. Identification of aberrant tau mRNA in brain tissue. AIzheimer's Rep. 4:145-150, 2001.
20･Tagawa M, Kano M, Okamura N, Higuchi M, Matsuda M, Mizuki Y, Arai H,
Iwata R, Fujii T, Komemushi S, Ido T, Itoh M, Sasaki H, Watanabe T, Yanai K.
Neuroimaglng Of histamine Hlィeceptor occupancy in human brain by
positron emission tomography (PET): A comparative study or ebastine, a
second一generation antihistamine, and (+)-chlorpheniramine, a classical
antihistamine. Brit. I. Clin. Pharmacol. 52:501-509, 2001.
21･Tashiro M, Itoh M, Kubota K, Kumano H, Masud MM, Moser EM, Arai H,
Sasaki H･ Relationship between trait anxiety, brain activlty and natural killer
cell activity ln Cancer Patients: A preliminary PET study･ Psychol0ncology
lO:541-546, 2001.
22･Arai H, Higuchi S, Higuchi M, Trojanowski Jq, Sasaki H. A
clinico-pathologlCal study･ Reyiew
23･Okamura N, Arai H, Maruyama M, H, Chiba H, Itoh M, Sasaki
l123I]Iodoamphetamine-SPECT in
Okamura N, Hara S, Itoh M, Shin 良-W,
case of dementia with Lewy bodies: A Series Dementia 1:14-15, 2002.
Higuchi M, Matsui T, Tanji H, Seki T, Hirai
H･ Combined analysts Of CSF-tau and
for a novel predictor ofAIzheimer's disease. Am. J. Psychiatry 159:474-476,
2002.
24･Matsushita S, Arai H. Okamura N, Ohmori T, Takasugi K, Matsui T, Maruyama M, Iwatsubo T, Higuchi S･ Clinical and bio一marker investigation of a patient
with a novel presenilin-1 mutation (A431V) in the mild impairment stage of AIzheimer's disease･ Biol･ Psychiatry 52:907-910, 2002･
25･Buerger K, Zinkowski 良, Teipel SJ, Tapiola T, Arai H, Blennow K, Andreasen N, Hofmann-Kiefer K,DeBernardis J, Kerkman D, McCulloch C, Kohnken R,Padberg F, Pirttila P, Schapiro MB, Rapoport SI,M61ler H-J, Davies P,
Hampel H･ Differential diagnosis of AIzheimer's disease with CSF tau proteinphosphorylated at threonine 23 I. Arch. NeuroI. 59: 1267-1272, 2002
26･Ebihara T, Yamaya M, Ohrui T, Arai H, Sasaki H･ Comparison of disabled older people in the USA and Japan. Geriatr. GerontoI.Int. 2:53-56, 2002. 27･ Ohrui T, Arai H, ichinose M, Matsui T, Yamaya M, Sasaki H･ Relationship
between asthma severlty and progression of AIzheimer's disease･ Thorax･
57:561, 2002.
28･Matsui T, Yamaya M, Ohrui T, Arai H, Sasaki H･ Sitting position to prevent aspiration in bed-ridden patients･ Gerontology 48: 194-195, 2002･
29･Buerger K, Zinkowski R, Teipel SJ, Arai H･ Differentiation between geriatric maJOr depression and AIzheimer's disease with CSF tau protein phosphorylated at threonine 231･ Am･ J･ Psychiatry 160:376-379･ 2003･
30･Tagawa M, Kano M, Okamura N, Higuchi M, Matsuda M, Mizuki Y. Arai H,
Fujii T, Komemushi S, Itoh M, Sasaki H, Watanabe T, Yanai K. Differential
cognitive effects of ebastine and (+)-chorphenilamine in healthy subjects:
co汀elation between cognltlVe impalrment and plasma drug concentrations･
Brit. ∫. CIin. Pharmacol. 53:296-304, 2002
31･XiaSheng Hu, Nobuyuki Okamura, Hirovuki Arai, Makoto Higuchi, Masahiro Maruyama, Masatoshi ltoh, Keiichiro Yamaguchi, Hidetada Sasaki･
Neuroanatomical correlates or low body weight in AIzheimer's disease･ Prog･
Neuro-psychopharmacoI&BioL Psychiatry 26: 128511289, 2002
32･Buerger K, Teipel SJ, Zimkowski 良, Blennow K. Arai H, Engel 良, Hofman K･ CSトtau protein phosphorylated at threonine 231 correlates with cognltlVe decline in MCI subjects. Neurology 59:627-629, 2002
33.Li Jq, Jia YX, Yamaya M, Arai H, Ohrui T, Sekizawa T, Sasaki H.
Neurochemical regulation of cough response to capsaicin in gulnea-plg.
Autonomic&Autacoid Pharmacology 22:57-63, 2002.
34･Ohara S, Tsuyuzaki ∫, Oide T, Arai H, Higuchi S, Hasegawa M, Iwatsubo T. A clinical and neuropathologcal study of an unusual case of sporadic tauopathy.
A variant of corticobasal degeneration? Neurosci. Lett. 300:84-88, 2002.
35･Shinkawa M, Yamaya M, Ohrui T, Arai H, Sasaki H. Depression in older people. Geriatr.&GerontoL. International 2:215-2 16, 2002.
36.Maruyama M, Arai H, Okamura N, Matsui M, Sasaki H. Biomarkers in subjects with amnestic mild cognltlVe impalrment. J. Am. Get･iatr. Sot. 2003 inpress.
37･Arai H, Matsui T, Maruyama M, Okamura N, Sasaki H. Classification of
dementias. Lancet 361:122711228, 2003.
38. Kanda A, Matsui T, Ebihara S, Arai H, Sasaki H. Periventricular white matter lesions and sleep alternation in older people. J. Am. Geriat. Soc. 51:432-433, 2003.
39･Seki T, Kurusu M, Haruko Tanji, Arai H, Sasaki H. Acupuncture and swallowing reflex in poststroke patients･ J･ Am･ Geriat･ Soc･ 51:726-727, 2003.
(2)口頭発表
Okamura N, Suemoto T, Suzuki M, Shiomitsu T, Shimadzu H, Arai H, Kudo Y, Sawada T･ New imaglng probes fわr in vivo labeling ofamyloid plaques and
neurofibrillary tangles･ 8暮h International Conference on AIzheimer,s disease
and related disorders. Stockholm, July20-25, 2002. (国際学会)
Maruyama M, Arai H, Tanji H, Higuchi M, Okamura N, Matsui T, Sugita M, Yoshida H, Matsushita S, Higuchi S, Sasaki H･ Cerebrosplnal nuid beta-amyloidト42 levels in the mild cognltlVe impalrment Stage OrAIzheimer's
disease.. Sth International Conference on AIzheimer,s disease and related
研究目的
アルツハイマー病脳では､時系列的にはアミロイドβ蛋白の凝集と沈着
がまず先行し､引き続いて10-20年のタイムラグを以って神経原繊維変
化の形成と神経細胞死が生じると考えられている｡従って､本来の意味
でのアルツハイマー病の早期診断の戦略としては､アミロイドβ蛋白の
凝集と沈着を反映するような診断マーカーを多少とも侵襲性を伴うとさ
れるCSF採取を通してではなく､簡便で非侵襲的な採血を通して得られ
る血液から樹立することが広く求められている｡このような診断マーカ
ーは､医療機関を受診する患者のみならず､広く一般住民を対象とする
ような健診などにおいても実施可能であり､その応用範囲は極めて大き
いと考えられる｡高血圧､糖尿病､高コレステロール血症は､血管障害
因子として血管性痴呆の危険因子であると同時にアルツハイマー病の危
険因子であることも指摘されている｡血渠ホモシステインは､簡便に測
定でき狭心症や脳梗塞などの虚血性疾患の発症に強く関係していること
が明らかとなった｡今回､アルツハイマー病患者において血柴ホモシス
テイン値を測定し､無症候性脳梗塞(Silent brain infarction)と血祭
ホモシステインの関連を明らかにした｡
研究計画及び研究方法_
(1)患者またはその家族の同意のもとに､空腹時にEDTA採血し､ 3000
rpm/15分間の遠心分離により血紫サンプルを得､-70oCに保存する｡
Association, 1994)またはNINCDS-ADRDAの診断基準(McKhannet al. Neurology24:939-944, 1984)に準じてこれにMRIなどによる画像診断
を加え行う｡ MRI上無症候性脳梗塞は､ 1)これまでに血管障害の発
作がない｡ 2) TlでLow,T2でHighの径3mm以上の病変を無症候性脳梗塞病変とし､これに対応するような神経学的異常所見を認めない｡
血液サンプル採取時の患者の認知機能を､ Mini一mental state examination により評価し､臨床的重症度と血渠ホモシステイン値の関連を検討する｡
(3)患者またはその家族の同意のもとに CSF を採取し､ CSトtauおよび Aβ1-42濃度を測定し､それぞれと血紫Aβ1142値の関連を検討する｡研究結果及び考察
DSM-ⅠⅤの診断基準を満たした141名のAD患者を139名の年齢と性を
マッチさせた地域在住高齢者と比較した｡141名のADの中で､47名(33%)にSBIが認められた｡ SBIを伴うADでは､ SBIのないADに比して有意に
年齢が高く､血祭ホモシステイン値が高値であった｡年齢を補正した多
変量解析では､血渠ホモシステイン値>11.4umol/Lでは､ SBIを有する
odds ratioは4.2倍(95% C.Ⅰ:1.7-10.5, p=0.002)に増加していた｡
しかし､ ApoE4遺伝子､高血圧､高コレステロール血症､喫煙習慣など
のvascular risk factorsは有意な危険因子ではなかった｡血渠ホモシ
ステイン値は､葉酸値と有意な逆相関を認めた｡また､血柴ホモシステ
アミロイド値とは相関しなかった｡ ｢結語｣ ADに伴う SBIは高ホモシス
テイン血症を危険因子としたユニークな血管障害と考えられたが､ ADの
直接的な危険因子とは考えにくい結果であった｡血渠ホモシステイン低
下療法が､ ADにおける血管障害を予防する上で新しい治療戦略となる可
能性が示唆された｡
参考文献(巻末参照)
1. Matsui T, Arai H, Yuzuriha T, Ya° H, Miura M, Hashimoto S, Higuchi S, Matsushita S, Morikawa M, Kato A, Sasaki H. Elevated plasma homocysteine levels and a risk for silent brain infarction in elderly people･ Stroke 32:1116-1119,2001.
2. Matsushita S, Arai H, Yuzuriha T, Kato M, Matsui T, Urakami K, Higuchi S･
No association between DLST gene and AIzheimer's disease or Wernicke-Korsakoff syndrome. Neurobiol. Aging 22:5691574, 2001 ･
3. Itoh N, Arai H, Urakami K, Ishiguro K, Ohno H, Hampel H, Buerger K, Wiltfang J, Otto M, Kretzschmar H, Moeller H-J, Imagawa M, Kohno H, Nakashima K, Kuzuhara S, Sasaki H, and lmahori K･ Large-scale, multi-center
study of cerebrosplnal fluid tau protein phosphorylated at serine 199 for the
antemortem diagnosis ofAIzheimer-s disease･ Anm･ Neurol･ 50:150-156, 2001 4. Urakami K, WadaK, Arai H, Sasaki H, Kanai M, Shoji M, Ishizu H, Kashihara
K, Yamamoto M, Tsuchiya-Ikemoto K, Morimatsu M, Takashima H, Nakagawa M, Kurokawa K, Maruyama H, Kaseda Y, Nakamura S, Hasegawa K, Oono H,
Hikase C, Ikeda K, Yamagata K, Wakutani Y, Takeshima T, Nakashima K･
Diagnostic slgnificance oftau protein in cerebrosplnal nuid什om patients with
corticobasal degeneration or progressive supranuclear palsy･ J･ NeuroI･ Sci･
183:95-98, 2001.
5. Maruyama M, Arai H, Sugita M, Tanji H, Higuchi M, Okamura N, Matsui T, Higuchi S, Matsushita S, Yoshida H, Sasaki H･ Cerebrosplnal fluid amyloid
β1_42 in the midl cognitive impairment stage of AIzheimer's disease･ Exp･
Neurol. 172:433-436, 2001.
6. Suzuki T, Arai H, Iwasaki K, Tanji H, Higuchi M, Okamura N, Matsui T, Maruyama M, Yabe T, Toriizuka K, Yamada H, Hanawa T, Ikarashi Y, Sasaki H･
A Japanese herbal medicine (Kami-Untan-To) in the treatment of AIzheimer's
7. Matsushita S, Arai札 Okamura N, Ohmori T, Takasugi K, Matsui T, Maruyama M, Iwatsubo T, Higuchi S. Clinical and bi0-marker investlgation of
a patient with a novel presenilin-1 mutation (A431V) in the mild impairment stage ofAIzheimer's disease. Biol. Psychiatry 52:907-910, 2002･
8. Buerger K, Zinkowski 良, Teipel SJ, Tapiola T, Arai H, Blennow 良, Andreasen N, Hofmann-Kiefer K,DeBernardis J, Kerkman D, McCulloch C, Kohnken R,Padberg F, Pirttila P, Schapiro MB, Rapoport SI,M61ler H-J,
Davies P, Hampel H. Differential diagnosis of AIzheimer.s disease with CSF
tau proteinphosphorylated at threonine 23l. Arch. NeuroI. 59:1267-1272, 2002
9. Buerger K, Zinkowski R, Teipel SJ, Arai H. Differentiation between geriatric maJOr depression and AIzheimer's disease with CSF tau protein phosphorylated at threonine 231. Am. I. Psychiatry 160:376-379. 2003.
10. XiaSheng Hu, Nobuyuki Okamura, Hiroyuki Arai, Makoto Higuchi, Masahiro Maruyama, Masatoshi ltoh, Keiichiro Yamaguchi, Hidetada Sasaki.
Neuroanatomical correlates of low body weight in AIzheimer's disease. Frog. Neuro-psychopharmacol&BioL. Psychiatt'y 26: 128511289, 2002
Ill Buerger K, Teipel SJ, Zinkowski R, Blennow K Arai H, Engel R, Hofman K.
CSF-tau protein phosphorylated at threonine 231 correlates with cognltlVe
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