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アルツハイマー型認知症

著者: 福井俊哉 かわさき記念病院病院長・昭和大学神経内科部門客員教授

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正/監修レビュー済:2021/07/21
患者向け説明資料

概要・推奨   

  1. 脳内炎症は正常老化でも認められるが、アルツハイマー病(AD)ではその程度が高度でありその病態に深く関わる。
  1. NSAIDsがAβの細胞毒性に対して抑制作用を有することは細胞培養・動物実験で確認されている。ヒトではNSAIDsの慢性関節炎などに対する長期使用がADの発症遅延、症状進行抑制に有効であるという疫学的事実がある(推奨度2)
  1. Amnestic-MCI(aMCI)の14%、non-amnestic MCIの8%が1年間でADに転換するとの観点から、aMCIのAD転換予防は重要な課題である(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
福井俊哉 : 特に申告事項無し[2021年]
監修:高橋裕秀 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、PART、LATEなどの新しい用語、最近の知見状況について加筆した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. アルツハイマー型認知症(AD)とは、病理学的にはアミロイドβの脳内沈着と異常リン酸化タウの細胞内沈着を特徴とし、生化学的には脳内アセチルコリンの減少を特徴とする認知症である。
  1. 1987年以降最も汎用されたアルツハイマー病診断基準は、National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association(NINCDS-ADRDA)によるものである。
  1. NINCDS-ADRDA 診断基準は2011年に改訂され、新たにNational Institute on Aging and the Alzheimer’s Association (NIA-AA)診断基準として発表された。
  1. NIA-AA診断基準では、バイオマーカーを重視した軽度認知障害(MCI)とアルツハイマー病(AD)の診断、また、研究用にMCI/AD発症前(preclinical stage)の診断の試みがなされている点が新しい。
  1. 認知症とは従来の能力からの低下により日常生活・職務が障害された状態であり、それがせん妄や精神病によるものではなく、認知低下が病歴、認知検査で確認でき、記憶・実行機能・視空間認知・言語・人格/行動のうち2項目以上の障害が認められるものをいう(NIA-AAによる認知症診断)。
  1. 認知症の定義(上記)が満たされ、さらに年齢にかかわらず潜行的に発症し、認知(健忘、言語、視空間認知、実行機能)の進行性悪化を認めた場合、AD(probable)と診断される(NIA-AAによるAD診断)。
  1. この診断基準では高度の補助診断方法(MRIやバイオマーカー)を用いない診断が可能となっている。
 
  1. Amnestic-MCI(aMCI)の14%、non-amnestic MCIの8%が1年間でADに転換する[1]との観点から、aMCIのAD転換予防は重要な課題である(推奨度2M)
  1. 769例のaMCI症例を対象にして、偽薬に対するドネペジルとビタミンE(Vit E)のAD転換抑制効果が検討された。3年の全試験期間を通したAD転換のオッズ比は、ドネペジル 0.80(p=.42)、Vit E 1.02(p=.91)であり、両薬ともにAD転換を有意に抑制するとはいえなかった。しかし、最初の1年間に限った場合はドネペジルが有意にAD転換を抑制し、さらにアポリポ蛋白E ε4遺伝子を1つでも有する症例では、ドネペジルのAD転換抑制効果は3年間にわたり認められた。一方、このサブ解析においてもVit EにはAD転換抑制効果は認められなかった[2]。また、MCIのAD転換予防に関して、2007年までに英文で発表された無作為比較試験(Randomized controlled study:RCT)のレビューでは、実薬群(ドネペジル、ガランタミン、リバスチグミンのいずれか)におけるAD転換率はで13%(2 年)~25%(3年)であり、偽薬の18%(2年)~28%(3年)よりも低率であるが統計学的有意性は認めていない[3]
 
  1. 「認知」とは「対象についての知識を獲得することを目的として、それに注意を向け、情報を積極的に収集し、対象に関する形・色(視覚)、音(聴覚)、触感(感覚)を知覚し、判断や推理を加え、記憶する一連の過程をいう。複合的な認知機能障害により日常生活や職業活動が支障された場合を「認知症」と称し、これらの認知障害を認知症の「中核症状」と称する(推奨度2O)
  1. 中核症状には、実行機能を主体とする前頭葉機能障害、記憶障害、失見当識、失語、失行、失認などが含まれる。
  1. 前頭葉機能には発動性、抑制、判断、推測、抽象化、実行機能など社会生活に必須な機能が含まれる。そのなかでも重要な実行機能とは、①動機・意図・構想・抽象化を駆使して「目標設定」し、②手段・手順を考案・評価・選択して「計画立案」し、③方向性を維持しながら、行為を開始・維持・修正して「計画実行」し、④到達度を推測しながら初期計画を「効果的に遂行」し、目標に達するために必要な機能をいう[4]
  1. 記憶はその持続時間から、即時記憶(数秒~数分)、近時記憶(数分~数週)、遠隔記憶(数カ月~数十年)と分類され、ADでは近似記憶が最も障害されやすい。一方、記憶はその内容からは陳述記憶(顕在記憶)と非陳述記憶(潜在記憶)に二分される[5]。陳述記憶とは言語で表現することの可能な記憶を指し、エピソード記憶と意味記憶の2種類がある。エピソード記憶とは、「いつ・どこで・だれが(に)・何を・なぜ・どうした」(5W1H)に関する記憶をいい、海馬・海馬傍回を含むPapez回路と前脳基底部が関与する。他方、意味記憶とは物事の概念・辞書的意味・知識に関する記憶であり、両側側頭葉先端と左側頭頭頂葉(言語性意味記憶)、右側頭後頭葉(視覚性意味記憶)が関与する。
  1. 非陳述記憶とは言葉では表現が困難な記憶を指し、その内容はプライミング(priming)と手続き記憶に大別される[6]。プライミングとは「意識されない見覚えの記憶」であり、次の行動を促進させる記憶である(商品宣伝が購買を促進した場合など)。手続き記憶とは体が覚える技能やスポーツに関する記憶であり、主に基底核・小脳が関与する。
  1. 失語は中枢性の言語機能障害であり、言語音を作るプログラミングの障害(発語失行)や構音障害(構音器官の運動障害による歪)とは区別される。概念を言語に置換して発話することが困難なものを運動失語(または表出型失語)、聴いた語音を言語として捉えて対応する概念と関連付けることの障害を感覚失語(または受容型失語)という。
  1. 失行とは行為の記憶が喪失・障害されることにより誤った行為をすることを指す。例えばバイバイや敬礼の模倣が「招き猫」の前足のような動きになる。なお、この行為異常は運動・感覚障害、小脳性運動失調症などに基づくものではないことが前提である。
  1. 失認とは、正しく知覚した対象の情報が対応する概念と結合しないため、対象の属性を認識できない状態をいう。例えば、視覚失認の場合、視覚情報が概念に到達しないために、見ている対象物が何であるかを認識できない。しかし、概念との連合が保たれている聴覚・触覚などを駆使すると対象物を瞬時に認識できる。失認と診断できるためには視覚・聴覚・体性感覚と意識が正常であることが前提となる。
 
  1. 周辺症状(BPSD: behavioral and psychological symptoms of dementia)は、認知症における精神・感情・行動障害などの非中核(認知)症状を指す[7]。BPSDの頻度と程度は認知症の重症度に概ね相関するが、特に全般性知能レベル低下と前頭葉機能障害の関わりが大きい[8][9](推奨度2O)
  1. 因子分析によりBPSDを分類すると、精神症状には幻覚、妄想、誤認症候群、せん妄などが、感情症状には抑うつ・不安、アパシー・意欲低下、易怒性などが、行動症状には徘徊・多動、食行動異常、不潔行為、仮性作業、昼夜逆転、夕暮れ症候群などが分類される[10]
  1. 精神症状
  1. 幻覚:実在しない対象が視覚的に(幻視)、聴覚的に(幻聴)知覚されることをいう。また、「背後に誰かがいる」、「亡くなった親族が家にいる」などの知覚的要素を伴わない「気配」は実体的意識性(leibhaftige Bewusstheit)[11]といわれ、同様に幻覚の範疇に入る。
  1. 妄想:「訂正困難な判断の誤り」と定義される。物盗られ妄想、嫉妬妄想、迫害(被害)妄想が多いが、心気妄想、罪業妄想、誇大妄想や自分の内臓が溶けてしまったなどの妄想(コタール症候群)がみられる。
  1. 誤認症候群:人物、物、場所などを誤認することをいう。人物に関する誤認症候群にはCapgras症候群(身近な人を他人の化身と誤認)[12]とFregoli症候群(特定の人がすべての人物に変装し自分を騙していると誤認)[13]がある。「幻の同居人」(phantom boarder)は他人が自宅内や玄関先にいると誤認するものである。一見、実体的意識性に類似するが誤認症候群に属する。
  1. せん妄:脳の脆弱性を基盤とする意識内容の変容を指し、せん妄を背景にさらにさまざまなBPSDが出現する。
  1. 感情症状
  1. 抑うつ状態・不安
  1. アパシー(無関心)・意欲低下:アパシー(apathy)の語源は「感情の消失」である。抑うつ気分、不安・焦燥、罪責感などを欠く点でうつ病とは異なる。
  1. 易怒性:患者本人に病識が残存する状態で、認知障害を非難されたり、事情を把握できないままに行動を制御・強制されることが引き金となりやすい。
  1. 行動異常
  1. 徘徊・多動:外出目的の忘却(記憶障害)、方向がわからない(視空間障害)、対処法がわからない(判断力障害)、それらによる不安焦燥に基づき、何とかしようと歩き回る状態を徘徊、そわそわ落ち着かない状態を多動という。
  1. 食行動異常:多食、頻食、盗食、非食品の異食、不食、拒食がある。
  1. 不潔行為:弄便、放尿、整容拒否などがある。排便後処理がわからない場合や便失禁後の不快感から、素手で便を処理しようすることを弄便という。トイレの場所がわからない場合や実際の頻尿により放尿が出現する。また、汚染された身体を洗浄することを拒否することも不潔行為に入る。
  1. 仮性作業:一見、目的に沿った作業にみえるが、実際は意味のない行為を繰り返すことをいう。整理すると称しながら引き出しの内容物の出し入れを繰り返すことがその典型である。
  1. 昼夜逆転(睡眠障害):夜間の覚醒・異常行動と昼間の傾眠傾向を指す。日中の活動性低下、昼寝、夜更かし、身体的不快(頻尿、瘙痒、逆流性食道炎、褥瘡疼痛など)、睡眠導入薬や向精神薬の誤用が原因であることが多い。
  1. 夕暮れ症候群:施設入所者の帰宅願望が夕方になると強くなり、多動、興奮、介護抵抗に至ることをいう。
 
  1. 脳内炎症は正常老化でも認められるが、アルツハイマー病(AD)ではその程度が高度でありその病態に深く関わる(推奨度2O)
  1. 脳内炎症には脳組織である神経細胞、ミクログリア(MG)、アストロサイト(AC)、ADの主病態であるベータアミロイド(Aβ)、および、グリア(MG、AC)が分泌する各種炎症惹起物質が作用し合って炎症を促進する悪循環をなす。AD治療薬として抗炎症薬が注目された所以である。
  1. 一般に、炎症とはストレス、外傷、感染などの外的侵襲に対して、細胞とそれが分泌する関連物質が反応性に活性化し、侵襲から生体を保護する過程をいう。神経炎症にはMG・AC・マクロファージ・リンパ球の活性化と、その結果生じるサイトカイン、ケモカイン、活性酸素などの炎症惹起物質の放出が関与する[14]。また、ノルエピネフリンとアセチルコリンは抗炎症作用と神経保護作用を有すると考えられているが、青斑核やマイネルト基底核の変性はそれらの物質の欠乏をもたらし、これらの核から投射を受けている部位の炎症を助長する[15]
  1. ADの場合、アミロイドカスケードにより生成されたAβは直接神経細胞を障害するだけではなく、MGを活性化することにより一酸化窒素、活性酸素、腫瘍壊死因子、インターロイキン、プロスタグランジンなどの炎症誘発物質の産生を誘導する。これらの炎症惹起物質により惹起された炎症機転を介してAβは間接的にAD病態の進行を促進する[16][17]。さらに、活性酸素の生体障害作用に対して生体側は解毒・障害修復機構をもって抗しようとするが、この侵襲と防衛の均衡が崩れた場合に酸化ストレスが生じる。高齢、虚血、高血糖、外傷などは酸化ストレスを増し、酸化ストレスはβ secretase活性を上げてAβ産生を増加させ、また産生されたAβは酸化ストレスを増大させる。この酸化ストレスとAβ産生増加の双方向性関わりが悪循環をなしAD病態の進行をさらに助長する[18]
 
  1. NSAIDsがAβの細胞毒性に対して抑制作用を有することは細胞培養・動物実験で確認されている。ヒトではNSAIDsの慢性関節炎などに対する長期使用がADの発症遅延、症状進行抑制に有効であるという疫学的事実[19]がある(推奨度2O)
  1. NSAIDsはミクログリア(MG)やアストロサイト(AC)内のシクロオキシゲナーゼ(cyclooxygenase: COX)を抑制し、炎症惹起関連物質であるプロスタグランジンの産生を減じて脳内炎症を抑えることを介してADの病態を抑制すると考えられる。さらに、COX-2特異的NSAIDsは抗炎症作用とは別にAβによる海馬シナプス機能抑制の阻止作用を有しており、この作用を介してAβ誘発性細胞障害を抑制する[20]。さらにNSAIDsはβ、γ-secretase機能を調整することによるAβ産生抑制、アミロイドベータ構造を変化させることによるAβ凝集抑制、Aβ貪食亢進などにより脳内Aβを減少させると考えられている[15][16][21]
  1. 他方、NSAIDsはPPARγ(peroxisome proliferator activated receptor gamma)を活性化することによりAD発症抑制・症状軽減に関わると推測されている[15][16][21]。PPARγはリガンドにより活性化される核受容体の1つでありiNOSのような炎症惹起関連分子の転写を抑制する。細胞培養や動物実験ではPPARγの活性化がAβレベルを下げることが確認されている[21]。臨床的にはPPARγアゴニストであるrosiglitazoneの24週投与がApoE ε4陰性の軽度~中等度AD症例における認知・機能改善を[22]、pioglitazoneの6カ月投与が糖尿病を合併した軽度ADの認知と頭頂葉血流を[23]改善させたと報告されている。
  1. NSAIDsの基礎的な資質に基づいてADに対する多くの治験が行われた。ADの症状改善・進行抑制に効果を認めた報告が少数あるが、期待に反してほとんどの治験で統計学的に有意な効果が認められていない。現時点ではNSAIDsのAD治療薬としての効果は否定的に考えられている[24]
病歴・診察のポイント  
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文献 

著者: S D Rountree, S C Waring, W C Chan, P J Lupo, E J Darby, R S Doody
雑誌名: Dement Geriatr Cogn Disord. 2007;24(6):476-82. doi: 10.1159/000110800. Epub 2007 Nov 8.
Abstract/Text BACKGROUND/AIMS: To evaluate baseline characteristics and conversion to dementia in mild cognitive impairment (MCI) subtypes.
METHODS: We prospectively evaluated conversion to dementia in 106 patients with amnestic MCI (A-MCI) as defined by Petersen's operationalized criteria on a paragraph recall task, amnestic-subthreshold MCI (AS-MCI) as defined by impairment on the ADAS-cog delayed word list recall with normal paragraph recall, nonamnestic MCI (NA-MCI) defined by a nonmemory domain, and in 27 patients with subjective memory loss who had no deficit on formal neuropsychological testing.
RESULTS: For all MCI subtypes, the 4-year conversion to dementia was 56% (14% annually) and to AD was 46% (11% annually). Conversion to AD in the A-MCI (56%) was similar to the rate in AS-MCI (50%). Conversion to AD in the A-MCI and AS-MCI combined was 56% (14% annually). Conversion to dementia in the NA-MCI was 52% (13% annually) and the majority converted to AD (62%).
CONCLUSIONS: All MCI subtypes are at risk of converting to AD if the groups are carefully defined by an abnormal psychometric domain. All subtypes except subjective memory loss converted to AD at higher than expected rates. Both the A-MCI and AS-MCI subtypes had a similarly high rate of conversion to AD. The deficit on a word list recall task may develop before an abnormality on delayed paragraph recall is evident, at least in some subjects.

(c) 2007 S. Karger AG, Basel.
PMID 17992015  Dement Geriatr Cogn Disord. 2007;24(6):476-82. doi: 10.・・・
著者: Ronald C Petersen, Ronald G Thomas, Michael Grundman, David Bennett, Rachelle Doody, Steven Ferris, Douglas Galasko, Shelia Jin, Jeffrey Kaye, Allan Levey, Eric Pfeiffer, Mary Sano, Christopher H van Dyck, Leon J Thal, Alzheimer's Disease Cooperative Study Group
雑誌名: N Engl J Med. 2005 Jun 9;352(23):2379-88. doi: 10.1056/NEJMoa050151. Epub 2005 Apr 13.
Abstract/Text BACKGROUND: Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease.
METHODS: In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function.
RESULTS: A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers.
CONCLUSIONS: Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.

Copyright 2005 Massachusetts Medical Society.
PMID 15829527  N Engl J Med. 2005 Jun 9;352(23):2379-88. doi: 10.1056/・・・
著者: Roberto Raschetti, Emiliano Albanese, Nicola Vanacore, Marina Maggini
雑誌名: PLoS Med. 2007 Nov 27;4(11):e338. doi: 10.1371/journal.pmed.0040338.
Abstract/Text BACKGROUND: Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.
METHODS AND FINDINGS: The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64-1.12), and 0.84 (0.57-1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).
CONCLUSIONS: The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.

PMID 18044984  PLoS Med. 2007 Nov 27;4(11):e338. doi: 10.1371/journal.・・・
著者: Endel Tulving
雑誌名: Annu Rev Psychol. 2002;53:1-25. doi: 10.1146/annurev.psych.53.100901.135114.
Abstract/Text Episodic memory is a neurocognitive (brain/mind) system, uniquely different from other memory systems, that enables human beings to remember past experiences. The notion of episodic memory was first proposed some 30 years ago. At that time it was defined in terms of materials and tasks. It was subsequently refined and elaborated in terms of ideas such as self, subjective time, and autonoetic consciousness. This chapter provides a brief history of the concept of episodic memory, describes how it has changed (indeed greatly changed) since its inception, considers criticisms of it, and then discusses supporting evidence provided by (a) neuropsychological studies of patterns of memory impairment caused by brain damage, and (b) functional neuroimaging studies of patterns of brain activity of normal subjects engaged in various memory tasks. I also suggest that episodic memory is a true, even if as yet generally unappreciated, marvel of nature.

PMID 11752477  Annu Rev Psychol. 2002;53:1-25. doi: 10.1146/annurev.ps・・・
著者: N J Cohen, L R Squire
雑誌名: Science. 1980 Oct 10;210(4466):207-10.
Abstract/Text Amnesic patients acquired a mirror-reading skill at a rate equivalent to that of matched control subjects and retained it for at least 3 months. The results indicate that the class of preserved learning skills in amnesia is broader than previously reported. Amnesia seems to spare information that is based on rules or procedures, as contrasted with information that is data-based or declarative--"knowing how rather than "knowing that." The results support the hypothesis that such a distinction is honored by the nervous system.

PMID 7414331  Science. 1980 Oct 10;210(4466):207-10.
著者: Josep Garre-Olmo, Secundino López-Pousa, Joan Vilalta-Franch, Manuel de Gracia Blanco, Antoni Bulbena Vilarrasa
雑誌名: J Alzheimers Dis. 2010;22(4):1157-67. doi: 10.3233/JAD-2010-101212.
Abstract/Text Behavioral and psychological symptoms of dementia (BPSD) are frequently observed in Alzheimer's disease (AD) and affect more than 80% of patients over the course of AD. The goal of this study was to establish a model for grouping the symptoms of BPSD into clinical syndromes. Over a 24-month period, an observational study was conducted using a population of ambulatory patients with AD of mild to moderate severity. The Neuropsychiatric Inventory (NPI) was administered to the patients' caregivers every 6 months. BPSD were grouped using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of the NPI scores of each assessment. The sample population consisted of 491 patients (70.9% women) with an average age of 75.2 years (SD=6.6). The five EFA suggested that there was a stable three-factor structure. According to the results of the EFA, three models of symptom grouping were adjusted using CFA methodology. The CFA model that satisfactorily grouped the NPI scores into three factors included a psychotic syndrome (hallucinations, delusions), an affective syndrome (depression, anxiety, irritability, agitation) and a behavior syndrome (euphoria, disinhibition, apathy, aberrant motor behavior). Based on our findings, we propose a model for grouping the BDSD in which there are core nuclear syndromes (psychotic and affective) as well as an unspecified behavior syndrome comprising satellite symptoms that may be related to the presence of the nuclear syndromes.

PMID 20930289  J Alzheimers Dis. 2010;22(4):1157-67. doi: 10.3233/JAD-・・・
著者: Michal Harciarek, Andrew Kertesz
雑誌名: Alzheimer Dis Assoc Disord. 2008 Apr-Jun;22(2):163-9. doi: 10.1097/WAD.0b013e3181641341.
Abstract/Text Although misidentification syndromes (MISs) have been often described in Alzheimer disease (AD), the prevalence of these phenomena in different neurodegenerative diseases has not been systematically studied. Three hundred ninety-two individuals with probable AD, 119 patients with the behavioral variety of frontotemporal dementia (FTD-bv), 101 patients with primary progressive aphasia, 24 subjects with semantic dementia, 18 subjects with corticobasal degeneration, 8 patients with progressive supranuclear palsy, 36 individuals with probable Lewy body dementia (DLB), and 26 subjects with Parkinson disease (PD) were the participants of this study. On the basis of a semistructured interview with both patients and their reliable caregivers, MIS was identified in 15.8% of cases with AD, 16.6% of patients with DLB, and in 8.3% of individuals with semantic dementia. The most frequent form of MIS was Capgras delusions, often accompanied by reduplication of place, phantom border phenomenon, or both. Although MIS typically appears in later stages of the disease, it can also occur surprisingly early in patients with AD. None of the patients with FTD-bv, primary progressive aphasia, corticobasal degeneration/supranuclear palsy, or PD developed MIS. Thus, our findings suggest that MISs are characteristic of AD and DLB, and tend to exclude FTD/Pick complex and PD.

PMID 18525289  Alzheimer Dis Assoc Disord. 2008 Apr-Jun;22(2):163-9. d・・・
著者: Manuel Fernández, Ana L Gobartt, Montse Balañá, COOPERA Study Group
雑誌名: BMC Neurol. 2010 Sep 28;10:87. doi: 10.1186/1471-2377-10-87. Epub 2010 Sep 28.
Abstract/Text BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are non-cognitive symptoms commonly associated to Alzheimer's disease (AD). The characterization of the clinical profile of AD patients might help to better understand disease evolution and to improve diagnosis and treatment. Thus, the aim of the present study is to describe the clinical profile of AD patients, and to correlate the presence of BPSD with the severity of the disease.
METHODS: A cross-sectional, observational and multicenter study was conducted at 115 centres in Spain. Patients suffering from AD with higher and lower BPSD scores (ADAS-Noncog score 26-50 and ≤25, respectively) were included. Demographic and clinical data were collected, and dementia severity was assessed by the Mini Mental State Examination (MMSE) [mild 27-21, moderate 20-11, severe ≤10]. The use of ADAS-Noncog in clinical practice was also explored.
RESULTS: A total of 1014 patients (463 with higher and 551 with lower BPSD scores) were included (mean age 77 ± 7 years, 65% women). Almost all patients (90%) had BPSD at inclusion, 17% of which reported psychotic outbreaks. The most prevalent symptoms were lack of concentration (56%), tremors (56%), depression (44%), lack of cooperation (36%), and delusions (32%). Patients with higher BPSD scores showed a significantly higher prevalence of psychotic symptoms (delusions, hallucinations, and delirium) and tremors, while emotional symptoms (tearfulness and apathy) predominated in patients with lower BPSD scores. MMSE and ADAS-Noncog scores were negatively associated (p = 0.0284), suggesting a correlation between cognitive impairment and BPSD. Lack of concentration and appetite change significantly correlated with MMSE (p = 0.0472 and p = 0.0346, respectively). Rivastigmine and donepezil were the first choice therapies in mild to moderate dementia. ADAS-Noncog was generally considered better or similar to other scales (82%), and 68% of the investigators were willing to use it in the future.
CONCLUSIONS: Our study shows that patients with AD have a high prevalence of noncognitive symptoms, and that cognitive impairment and BPSD are correlated. Therefore, ADAS-Noncog is a useful evaluation tool.

PMID 20920205  BMC Neurol. 2010 Sep 28;10:87. doi: 10.1186/1471-2377-1・・・
著者: Sulagna Das, Anirban Basu
雑誌名: J Neurosci Res. 2008 May 1;86(6):1199-208. doi: 10.1002/jnr.21585.
Abstract/Text Any pathological perturbation to the brain provokes a cascade of molecular and cellular events, which manifests in the form of microglial activation and release of various proinflammatory molecules. This eventually culminates in a profound neuroinflammatory reaction that characterizes the brain's response to stress, injury, or infection. The inflammatory cascade is an attempt by the system to eliminate the challenge imposed on the brain, clear the system of the dead and damaged neurons, and rescue the normal functioning of this vital organ. However, during the process of microglial activation, the proinflammatory mediators released exert certain detrimental effects, and neural stem cells and progenitor cells are likely to be affected. Here we review how the proliferation, maturation, and migration of the neural stem cells are modulated under such an inflammatory condition. The fate of the noncommitted neural stem cells and its differentiation potency are often under strict regulation, and these proinflammatory mediators seem to disrupt this critical balance and finely tune the neurogenesis pattern in the two niches of neurogenesis, the subventricular zone and the subgranular zone of the hippocampus. Moreover, the migration ability of these stem cells, which is important for localization to the proper site, is also affected in a major way by the chemokines released following inflammation.

2007 Wiley-Liss, Inc.
PMID 18058947  J Neurosci Res. 2008 May 1;86(6):1199-208. doi: 10.1002・・・
著者: Michael T Heneka, M Kerry O'Banion, Dick Terwel, Markus Peter Kummer
雑誌名: J Neural Transm. 2010 Aug;117(8):919-47. doi: 10.1007/s00702-010-0438-z. Epub 2010 Jul 15.
Abstract/Text Generation of neurotoxic amyloid beta peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer's disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or gamma-secretase inhibition and activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.

PMID 20632195  J Neural Transm. 2010 Aug;117(8):919-47. doi: 10.1007/s・・・
著者: Young-Jung Lee, Sang Bae Han, Sang-Yoon Nam, Ki-Wan Oh, Jin Tae Hong
雑誌名: Arch Pharm Res. 2010 Oct;33(10):1539-56. doi: 10.1007/s12272-010-1006-7. Epub 2010 Oct 30.
Abstract/Text Alzheimer's disease (AD) is the most common form of dementia. It is characterized by extracellular deposition of a specific protein, beta-amyloid peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. Although the pathophysiologic mechanism is not fully established, inflammation appears to be involved. Neuroinflammation has been known to play a critical role in the pathogenesis of chronic neurodegenerative disease in general, and in AD in particular. Numerous studies show the presence of a number of markers of inflammation in the AD brain: elevated inflammatory cytokines and chemokines, and accumulation of activated microglia in the damaged regions. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between neuroinflammation and AD pathogenesis. The aim of this review is (1) to assess the association between neuroinflammation and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD.

PMID 21052932  Arch Pharm Res. 2010 Oct;33(10):1539-56. doi: 10.1007/s・・・
著者: D Praticò, J Q Trojanowski
雑誌名: Neurobiol Aging. 2000 May-Jun;21(3):441-5; discussion 451-3.
Abstract/Text
PMID 10858591  Neurobiol Aging. 2000 May-Jun;21(3):441-5; discussion 4・・・
著者: Michela Guglielmotto, Luca Giliberto, Elena Tamagno, Massimo Tabaton
雑誌名: Front Aging Neurosci. 2010;2:3. doi: 10.3389/neuro.24.003.2010. Epub 2010 Feb 9.
Abstract/Text Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting the elderly population. Mechanistically, the major cause of the disease bases on the altered processing of the amyloid-beta (Abeta) precursor protein (APP), resulting in the accumulation and aggregation of neurotoxic forms of Abeta. Abeta derives from the sequential proteolytic cleavage of the beta- and gamma-secretases on APP. The causes of Abeta accumulation in the common sporadic form of AD are not completely known, but they are likely to include oxidative stress (OS). OS and Abeta are linked to each other since Abeta aggregation induces OS in vivo and in vitro, and oxidant agents increase the production of Abeta. Moreover, OS produces several effects that may contribute to synaptic function and cell death in AD. We and others have shown that the expression and activity of beta-secretase (named BACE1; beta-site APP cleaving enzyme) is increased by oxidant agents and by lipid peroxidation product 4-hydroxynonenal and that there is a significant correlation between BACE1 activity and oxidative markers in sporadic AD. OS results from several cellular insults such as aging, hyperglycemia, hypoxic insults that are all well known risk factors for AD development. Thus, our data strengthen the hypothesis that OS is a basic common pathway of Abeta accumulation, common to different AD risk factors.

PMID 20552043  Front Aging Neurosci. 2010;2:3. doi: 10.3389/neuro.24.0・・・
著者: P L McGeer, M Schulzer, E G McGeer
雑誌名: Neurology. 1996 Aug;47(2):425-32.
Abstract/Text Alzheimer's disease (AD) lesions are characterized by the presence of numerous inflammatory proteins. This has led to the hypothesis that brain inflammation is a cause of neuronal injury in AD and that anti-inflammatory drugs may act as protective agents. Seventeen epidemiologic studies from nine different countries have now been published in which arthritis, a major indication for the use of anti-inflammatory drugs, or anti-inflammatory drugs themselves have been considered as risk factors for AD. Both factors appear to be associated with a reduced prevalence of AD. The small size of most studies has limited their individual statistical significance, but similarities in design have made it possible to evaluate combined results. We have used established methods of statistical meta-analysis to estimate the overall chance of individuals exposed to arthritis or anti-inflammatory drugs developing AD as compared with the general population. Seven case-control studies with arthritis as the risk factor yielded an overall odds ratio of 0.556 (p < 0.0001), while four case-control studies with steroids yielded odds ratios of 0.656 (p = 0.049) and three case-control studies with nonsteroidal anti-inflammatory drugs (NSAIDs) yielded an odds ratio of 0.496 (p = 0.0002). When NSAIDs and steroids were combined into a single category of anti-inflammatory drugs, the odds ratio was 0.556 (p < 0.0001). Population-based studies were less similar in design than case-control studies, complicating the process of applying statistical meta-analytical techniques. Nevertheless, population-based studies with rheumatoid arthritis and NSAID use as risk factors strongly supported the results of case-control studies. These data suggest anti-inflammatory drugs may have a protective effect against AD. Controlled clinical trials will be necessary to test this possibility.

PMID 8757015  Neurology. 1996 Aug;47(2):425-32.
著者: Linda A Kotilinek, Marcus A Westerman, Qinwen Wang, Kimberly Panizzon, Giselle P Lim, Agnes Simonyi, Sylvain Lesne, Agnieszka Falinska, Linda H Younkin, Steven G Younkin, Michael Rowan, James Cleary, Roi Ann Wallis, Grace Y Sun, Greg Cole, Sally Frautschy, Roger Anwyl, Karen H Ashe
雑誌名: Brain. 2008 Mar;131(Pt 3):651-64. doi: 10.1093/brain/awn008.
Abstract/Text Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid precursor protein (APP) have led to two proposed mechanisms by which NSAIDs may protect against Alzheimer's disease: one, the selective lowering of Abeta42 by a subset of NSAIDs; and two, the reduction of inflammation. Although Alzheimer's disease is a disorder of brain and synaptic function, the effects of NSAIDs on Abeta-mediated suppression of synaptic plasticity and memory function have never been reported. We therefore investigated how three different NSAIDs, chosen for their distinct effects on Abeta42 production and the inhibition of the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, affect memory function and synaptic plasticity. By focusing upon brain and synapse function, we made novel observations about the effects of NSAIDs on Abeta-mediated neural processes. Here we report that the selective inhibition of COX-2, but not COX-1, acutely prevented the suppression of hippocampal long-term plasticity (LTP) by Abeta. The non-selective NSAIDs, ibuprofen and naproxen, and a selective COX-2 inhibitor, MF-tricyclic, each restored memory function in Tg2576 mice over-expressing APP, and also blocked Abeta-mediated inhibition of LTP. There was no advantage of ibuprofen, a selective Abeta42-lowering agent (SALA), over the non-SALAs, naproxen and MF-tricyclic. The beneficial effects on memory did not depend upon lowered levels of Abeta42 or the inflammatory cytokines, tumour necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Intriguingly, improved memory function was inversely related to prostaglandin E2 (PGE2) levels. Conversely, exogenous PGE2 prevented the restorative effects of COX-2 inhibitors on LTP. The data indicate that the inhibition of COX-2 blocks Abeta-mediated suppression of LTP and memory function, and that this block occurs independently of reductions in Abeta42 or decreases in inflammation. The results lead us to propose a third possible mechanism by which NSAIDs may protect against Alzheimer's disease, involving the blockade of a COX-2-mediated PGE2 response at synapses.

PMID 18292081  Brain. 2008 Mar;131(Pt 3):651-64. doi: 10.1093/brain/aw・・・
著者: Magdalena Sastre, Thomas Klockgether, Michael T Heneka
雑誌名: Int J Dev Neurosci. 2006 Apr-May;24(2-3):167-76. doi: 10.1016/j.ijdevneu.2005.11.014. Epub 2006 Feb 10.
Abstract/Text There is compelling evidence that Alzheimer's disease (AD) amyloid-beta (Abeta) deposition is associated with a local inflammatory response, which is initiated by the activation of microglia and the recruitment of astrocytes. These cells secrete a number of cytokines and neurotoxic products that may contribute to neuronal degeneration and cell death. It has been documented that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk for developing AD and delay the onset of the disease. The mechanism behind these NSAIDs is still controversial and several hypotheses have been raised, including changes in the amyloid precursor protein (APP) metabolism, in Abeta aggregation and a decrease in inflammatory mediators. Recently, it was proposed that some NSAIDs might activate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma belongs to a family of nuclear receptors that are able to regulate the transcription of pro-inflammatory molecules, such as iNOS. The activation of PPAR-gamma has been recently reported to reduce Abeta levels in cell culture and AD animal models. The implication of PPAR-gamma in the control of Abeta-induced inflammation suggests a new target for AD therapy and emphasize the contribution of neuroinflammatory mechanisms to the pathogenesis of AD.

PMID 16472958  Int J Dev Neurosci. 2006 Apr-May;24(2-3):167-76. doi: 1・・・
著者: M E Risner, A M Saunders, J F B Altman, G C Ormandy, S Craft, I M Foley, M E Zvartau-Hind, D A Hosford, A D Roses, Rosiglitazone in Alzheimer's Disease Study Group
雑誌名: Pharmacogenomics J. 2006 Jul-Aug;6(4):246-54. doi: 10.1038/sj.tpj.6500369. Epub 2006 Jan 31.
Abstract/Text Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE epsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE epsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE epsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE epsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE epsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

PMID 16446752  Pharmacogenomics J. 2006 Jul-Aug;6(4):246-54. doi: 10.1・・・
著者: Tomohiko Sato, Haruo Hanyu, Kentaro Hirao, Hidekazu Kanetaka, Hirofumi Sakurai, Toshihiko Iwamoto
雑誌名: Neurobiol Aging. 2011 Sep;32(9):1626-33. doi: 10.1016/j.neurobiolaging.2009.10.009. Epub 2009 Nov 17.
Abstract/Text To test the effects of the PPAR-γ agonist pioglitazone on cognition, regional cerebral blood flow (rCBF), and plasma levels of Aβ40 and Aβ42, we conducted a 6-month, randomized, open-controlled trial in patients with mild Alzheimer disease (AD) accompanied with type II diabetes mellitus. We randomly assigned 42 patients to either the group treated with 15-30 mg pioglitazone daily (n=21, pioglitazone group) or not (n=21, control group). The pioglitazone group improved cognition and rCBF in the parietal lobe, while the control group showed no such improvement. The plasma Aβ40/Aβ42 ratio increased in the control group, but showed no significant change in the pioglitazone group. Both groups showed good control of diabetes during the study. In addition, pioglitazone treatment resulted in a decrease in fasting plasma insulin levels, indicating enhanced insulin sensitivity. The results of this pilot study demonstrated that pioglitazone exhibited cognitive and functional improvements, and stabilization of the disease in diabetic patients with AD. Pioglitazone may offer a novel strategy for the treatment of AD.

Copyright © 2009 Elsevier Inc. All rights reserved.
PMID 19923038  Neurobiol Aging. 2011 Sep;32(9):1626-33. doi: 10.1016/j・・・
著者: Robert C Green, Lon S Schneider, David A Amato, Andrew P Beelen, Gordon Wilcock, Edward A Swabb, Kenton H Zavitz, Tarenflurbil Phase 3 Study Group
雑誌名: JAMA. 2009 Dec 16;302(23):2557-64. doi: 10.1001/jama.2009.1866.
Abstract/Text CONTEXT: Amyloid-beta peptide (Abeta(42)) has been implicated in the pathogenesis of Alzheimer disease (AD). Tarenflurbil, a selective Abeta(42)-lowering agent, demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients in an earlier phase 2 trial.
OBJECTIVE: To determine the efficacy, safety, and tolerability of tarenflurbil.
DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, double-blind, placebo-controlled trial enrolling patients with mild AD was conducted at 133 trial sites in the United States between February 21, 2005, and April 30, 2008. Concomitant treatment with cholinesterase inhibitors or memantine was permitted.
INTERVENTION: Tarenflurbil, 800 mg, or placebo, administered twice a day.
MAIN OUTCOME MEASURES: Co-primary efficacy end points were the change from baseline to month 18 in total score on the subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, 80-point version) and Alzheimer Disease Cooperative Studies-activities of daily living (ADCS-ADL) scale. Additional prespecified slope analyses explored the possibility of disease modification.
RESULTS: Of the 1684 participants randomized, 1649 were included in the analysis, and 1046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary outcomes (difference in change from baseline to month 18 vs placebo, based on least squares means: 0.1 for ADAS-Cog; 95% CI, -0.9 to 1.1; P = .86 and -0.5 for ADCS-ADL; 95% CI, -1.9 to 0.9; P = .48) using an intent-to-treat analysis. No significant differences occurred in the secondary outcomes. The ADAS-Cog score decreased by 7.1 points over 18 months. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections.
CONCLUSION: Tarenflurbil did not slow cognitive decline or the loss of activities of daily living in patients with mild AD.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00105547.

PMID 20009055  JAMA. 2009 Dec 16;302(23):2557-64. doi: 10.1001/jama.20・・・
著者: Guy M McKhann, David S Knopman, Howard Chertkow, Bradley T Hyman, Clifford R Jack, Claudia H Kawas, William E Klunk, Walter J Koroshetz, Jennifer J Manly, Richard Mayeux, Richard C Mohs, John C Morris, Martin N Rossor, Philip Scheltens, Maria C Carrillo, Bill Thies, Sandra Weintraub, Creighton H Phelps
雑誌名: Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.jalz.2011.03.005. Epub 2011 Apr 21.
Abstract/Text The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

Copyright © 2011. Published by Elsevier Inc.
PMID 21514250  Alzheimers Dement. 2011 May;7(3):263-9. doi: 10.1016/j.・・・
著者: B Reisberg, S H Ferris, M J de Leon, A Kluger, E Franssen, J Borenstein, R C Alba
雑誌名: Prog Clin Biol Res. 1989;317:23-41.
Abstract/Text A series of studies published over the past 6 years now permit a relatively precise description of the temporal course of Alzheimer's disease (AD). Initially, 7 global stages of CNS aging and AD were described. Subsequently, data on the stage specific relationship between these stages and widely employed mental status, psychometric, and other assessment measures were collected. Longitudinal studies helped to clarify the borders between normal CNS aging and AD using these measures. Other studies described functioning and self-care correlates of the 7 global stages. These were ultimately divisible into 16 clearly defined, ordinal functional stages. Empirical longitudinal observations permitted the description of the mean temporal course of each of the 16 functional stages of aging and AD. The cross-sectional stage specific data on mental status and other measures can now be applied to the mean temporal course observations and the validity of the temporal estimates forwarded can be investigated in detail. Etiologic hypotheses based upon the observed phenomenologic and temporal course of AD are discussed.

PMID 2690101  Prog Clin Biol Res. 1989;317:23-41.
著者: Marilyn S Albert, Steven T DeKosky, Dennis Dickson, Bruno Dubois, Howard H Feldman, Nick C Fox, Anthony Gamst, David M Holtzman, William J Jagust, Ronald C Petersen, Peter J Snyder, Maria C Carrillo, Bill Thies, Creighton H Phelps
雑誌名: Alzheimers Dement. 2011 May;7(3):270-9. doi: 10.1016/j.jalz.2011.03.008. Epub 2011 Apr 21.
Abstract/Text The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

Copyright © 2011 The Alzheimer's Association. All rights reserved.
PMID 21514249  Alzheimers Dement. 2011 May;7(3):270-9. doi: 10.1016/j.・・・
著者: R S Doody, S H Ferris, S Salloway, Y Sun, R Goldman, W E Watkins, Y Xu, A K Murthy
雑誌名: Neurology. 2009 May 5;72(18):1555-61. doi: 10.1212/01.wnl.0000344650.95823.03. Epub 2009 Jan 28.
Abstract/Text BACKGROUND: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms.
METHODS: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function.
RESULTS: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%).
CONCLUSIONS: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

PMID 19176895  Neurology. 2009 May 5;72(18):1555-61. doi: 10.1212/01.w・・・
著者: S Salloway, S Ferris, A Kluger, R Goldman, T Griesing, D Kumar, S Richardson, Donepezil 401 Study Group
雑誌名: Neurology. 2004 Aug 24;63(4):651-7.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI).
METHODS: A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician's Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations.
RESULTS: Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient.
CONCLUSION: Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.

PMID 15326237  Neurology. 2004 Aug 24;63(4):651-7.
著者: Serge Gauthier, Barry Reisberg, Michael Zaudig, Ronald C Petersen, Karen Ritchie, Karl Broich, Sylvie Belleville, Henry Brodaty, David Bennett, Howard Chertkow, Jeffrey L Cummings, Mony de Leon, Howard Feldman, Mary Ganguli, Harald Hampel, Philip Scheltens, Mary C Tierney, Peter Whitehouse, Bengt Winblad, International Psychogeriatric Association Expert Conference on mild cognitive impairment
雑誌名: Lancet. 2006 Apr 15;367(9518):1262-70. doi: 10.1016/S0140-6736(06)68542-5.
Abstract/Text Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.

PMID 16631882  Lancet. 2006 Apr 15;367(9518):1262-70. doi: 10.1016/S01・・・
著者: E K Perry, R H Perry, G Blessed, B E Tomlinson
雑誌名: Neuropathol Appl Neurobiol. 1978 Jul-Aug;4(4):273-7.
Abstract/Text Acetyl- and butyryl-cholinesterase activities have been measured biochemically in normal brain tissue, in senile dementia of Alzheimer type and in mental disorders without Alzheimer-type abnormalities. Acetylcholinesterase was significantly reduced and butyrylcholinesterase significantly increased, compared with the normal, in the hippocampus and temporal cortex of the Alzheimer cases. No significant enzyme changes were seen in the other diseases investigated including multi-infarct dementia, schizophrenia and depression. There was no correlation between age and acetylcholinesterase activity, but a significant positive correlation between the butyrylcholinesterase activities with increasing age (60-90 years) was found in the hippocampus. The possible connection between cholinergic system pathology and these cholinesterase abnormalities in Alzheimer dementia is discussed.

PMID 703927  Neuropathol Appl Neurobiol. 1978 Jul-Aug;4(4):273-7.
著者: Aurelia Santoro, Paola Siviero, Nadia Minicuci, Elena Bellavista, Michele Mishto, Fabiola Olivieri, Francesca Marchegiani, Andrea Maria Chiamenti, Luisa Benussi, Roberta Ghidoni, Benedetta Nacmias, Silvia Bagnoli, Andrea Ginestroni, Osvaldo Scarpino, Emidio Feraco, Walter Gianni, Guido Cruciani, Roberto Paganelli, Angelo Di Iorio, Mario Scognamiglio, Luigi Maria Edoardo Grimaldi, Carlo Gabelli, Sandro Sorbi, Giuliano Binetti, Gaetano Crepaldi, Claudio Franceschi
雑誌名: CNS Drugs. 2010 Feb;24(2):163-76. doi: 10.2165/11310960-000000000-00000.
Abstract/Text Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer's disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial. To compare the effects of three AChEIs, donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), in an Italian national, prospective, observational study representative of the 'real world' clinical practice of AChEI treatment for AD. 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants. No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2-3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. ApoE epsilon4 allele did not influence the effect of drug therapy. Over a 36-week follow-up period, no significant difference in the effects of donepezil, galantamine and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of apoE-genotyped patients with mild to moderate AD recruited within the framework of a national project representative of the scenario usually encountered in actual clinical practice in Italy. The limitations (possibility of administration of lower drug doses than are used in clinical trials, relatively short follow-up period and the lack of randomization) and strengths (large number of patients, concomitant observation of the three drugs and the number of parameters assessed, including apoE genotype) of the present study are acknowledged. Our type of naturalistic study should complement clinical trials because 'real world' practice operates in the face of the numerous variables (e.g. health status and co-morbidities) associated with a complex disease such as AD in elderly people.

PMID 20088621  CNS Drugs. 2010 Feb;24(2):163-76. doi: 10.2165/11310960・・・
著者: Gordon Wilcock, Ian Howe, Hilary Coles, Sean Lilienfeld, Luc Truyen, Young Zhu, Roger Bullock, Paul Kershaw, GAL-GBR-2 Study Group
雑誌名: Drugs Aging. 2003;20(10):777-89.
Abstract/Text OBJECTIVE: To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer's disease.
PATIENTS AND STUDY DESIGN: This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer's disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks.
MAIN OUTCOME MEASURES: The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed.
RESULTS: BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients' scores on the MMSE at week 52 did not differ significantly from baseline (-0.52 +/- 0.39, p < 0.5 vs baseline), whereas donepezil patients' scores deteriorated significantly from baseline (-1.58 +/- 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < or = 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12-18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 +/- 0.80 versus baseline, compared with an increase of 4.08 +/- 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p < or = 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments. Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.
CONCLUSIONS: Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.

PMID 12875613  Drugs Aging. 2003;20(10):777-89.
著者: Roger Bullock, Jacques Touchon, Howard Bergman, Giuseppe Gambina, Yunsheng He, Günter Rapatz, Jennifer Nagel, Roger Lane
雑誌名: Curr Med Res Opin. 2005 Aug;21(8):1317-27. doi: 10.1185/030079905X56565.
Abstract/Text OBJECTIVES: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period.
METHODS: Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs.
RESULTS: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment.
CONCLUSIONS: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.

PMID 16083542  Curr Med Res Opin. 2005 Aug;21(8):1317-27. doi: 10.1185・・・
著者: S Bakchine, H Loft
雑誌名: J Alzheimers Dis. 2008 Feb;13(1):97-107.
Abstract/Text Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist currently approved for the treatment of moderate to severe Alzheimer's disease (AD). A 24-week, double-blind, placebo-controlled, study (Study 99679) conducted in Europe evaluated the efficacy and tolerability of 20 mg/day memantine in patients with mild to moderate AD. Patients were randomised to either memantine or placebo in a 2:1 ratio. Efficacy was primarily assessed as change from baseline in ADAS-cog and CIBIC-plus score. Of 470 patients randomised and treated (memantine, n=318; placebo, n=152), 85% and 91% completed the study. Memantine-treated patients showed statistically significant improvement relative to placebo at weeks 12 and 18, and numerical superiority at week 24 on both efficacy scales. The lack of significance at week 24 was attributed to an unexpectedly high placebo response. Memantine was well tolerated with an adverse event profile similar to placebo. The data presented support the efficacy of memantine in mild to moderate AD.

PMID 18334761  J Alzheimers Dis. 2008 Feb;13(1):97-107.
著者: Elaine R Peskind, Steven G Potkin, Nunzio Pomara, Brian R Ott, Stephen M Graham, Jason T Olin, Scott McDonald
雑誌名: Am J Geriatr Psychiatry. 2006 Aug;14(8):704-15. doi: 10.1097/01.JGP.0000224350.82719.83.
Abstract/Text OBJECTIVE: The objective of this study was to compare the efficacy and safety of the moderate-affinity, uncompetitive N-methyl-d-aspartate receptor antagonist, memantine, versus placebo in patients with mild to moderate Alzheimer disease (AD).
METHOD: This was a randomized, double-blind, placebo-controlled clinical trial conducted at 42 U.S. sites. Participants were 403 outpatients with mild to moderate AD and Mini-Mental State Examination scores of 10-22 randomized to memantine (20 mg/day; N=201) or placebo (N=202) for 24 weeks. Primary outcomes were change from baseline at 24 weeks on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), a measure of cognition, and on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), a global measure. Secondary outcomes included change on the Neuropsychiatric Inventory (NPI) and the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL(23)), measures of behavior and function, respectively.
RESULTS: Most (82.4%) participants completed the trial. Memantine resulted in significantly better outcomes than placebo on measures of cognition, global status, and behavior when based on the protocol-specified primary last observation carried forward imputation as well as a mixed-models repeated-measures approach applied to the continuous outcomes. Treatment discontinuations because of adverse events for memantine versus placebo were 19 (9.5%) and 10 (5.0%), respectively.
CONCLUSIONS: These results support the safety and efficacy of memantine for the treatment of mild to moderate AD.

PMID 16861375  Am J Geriatr Psychiatry. 2006 Aug;14(8):704-15. doi: 10・・・
著者: Anton P Porsteinsson, George T Grossberg, Jacobo Mintzer, Jason T Olin, Memantine MEM-MD-12 Study Group
雑誌名: Curr Alzheimer Res. 2008 Feb;5(1):83-9.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of memantine in patients with mild to moderate Alzheimer's disease (AD) receiving cholinesterase inhibitor (ChEI) treatment.
METHODS: Participants (N= 433) with probable AD, Mini-Mental State Exam (MMSE) scores between 10-22 (inclusive), and concurrent stable use of ChEIs (donepezil, rivastigmine, galantamine) were randomized to placebo or memantine (20 mg once daily) for 24 weeks. Primary outcomes were changes from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and on Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) score. Secondary measures comprised the 23-item Alzheimer Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL(23)), Neuropsychiatric Inventory (NPI), and MMSE.
RESULTS: At the end of the trial, there were no statistically significant differences between the memantine- and placebo group on primary and secondary outcome measures. The incidence of adverse events (AEs) was similar between the two groups, with no AE occurring in more than 5% of memantine-treated patients and at a rate twice that of the placebo group.
CONCLUSIONS: In this trial, memantine did not show an advantage over placebo based on protocol-specified primary or secondary analyses in patients with mild to moderate AD on stable ChEI regimens. There were no significant differences in tolerability and safety between the memantine- and placebo groups.

PMID 18288936  Curr Alzheimer Res. 2008 Feb;5(1):83-9.
著者: Barry Reisberg, Rachelle Doody, Albrecht Stöffler, Frederick Schmitt, Steven Ferris, Hans Jörg Möbius, Memantine Study Group
雑誌名: N Engl J Med. 2003 Apr 3;348(14):1333-41. doi: 10.1056/NEJMoa013128.
Abstract/Text BACKGROUND: Overstimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate is implicated in neurodegenerative disorders. Accordingly, we investigated memantine, an NMDA antagonist, for the treatment of Alzheimer's disease.
METHODS: Patients with moderate-to-severe Alzheimer's disease were randomly assigned to receive placebo or 20 mg of memantine daily for 28 weeks. The primary efficacy variables were the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev). The secondary efficacy end points included the Severe Impairment Battery and other measures of cognition, function, and behavior. Treatment differences between base line and the end point were assessed. Missing observations were imputed by using the most recent previous observation (the last observation carried forward). The results were also analyzed with only the observed values included, without replacing the missing values (observed-cases analysis).
RESULTS: Two hundred fifty-two patients (67 percent women; mean age, 76 years) from 32 U.S. centers were enrolled. Of these, 181 (72 percent) completed the study and were evaluated at week 28. Seventy-one patients discontinued treatment prematurely (42 taking placebo and 29 taking memantine). Patients receiving memantine had a better outcome than those receiving placebo, according to the results of the CIBIC-Plus (P=0.06 with the last observation carried forward, P=0.03 for observed cases), the ADCS-ADLsev (P=0.02 with the last observation carried forward, P=0.003 for observed cases), and the Severe Impairment Battery (P<0.001 with the last observation carried forward, P=0.002 for observed cases). Memantine was not associated with a significant frequency of adverse events.
CONCLUSIONS: Antiglutamatergic treatment reduced clinical deterioration in moderate-to-severe Alzheimer's disease, a phase associated with distress for patients and burden on caregivers, for which other treatments are not available.

Copyright 2003 Massachusetts Medical Society
PMID 12672860  N Engl J Med. 2003 Apr 3;348(14):1333-41. doi: 10.1056/・・・
著者: Christopher H van Dyck, Pierre N Tariot, Barnett Meyers, E Malca Resnick, Memantine MEM-MD-01 Study Group
雑誌名: Alzheimer Dis Assoc Disord. 2007 Apr-Jun;21(2):136-43. doi: 10.1097/WAD.0b013e318065c495.
Abstract/Text This study examined the efficacy and safety of memantine monotherapy in patients with moderate-to-severe Alzheimer disease (AD). Patients not receiving a cholinesterase inhibitor (N=350) were randomized to receive memantine (20 mg/d) or placebo during this 24-week, double-blind, placebo-controlled trial. Prospectively defined analyses failed to demonstrate a statistically significant benefit of memantine treatment compared with placebo on the Severe Impairment Battery (SIB) at week 24 end point, although a significant advantage was observed for memantine at weeks 12 and 18. The 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL19) did not differ significantly between groups in any analysis. Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus) did not significantly favor memantine at week 24 despite a significant advantage for memantine at weeks 12 and 18. Other secondary outcomes showed no significant treatment differences. Post hoc analyses of potentially confounding covariates and alternative methods of imputing missing data did not substantially alter the results. Because of the violations of normality assumptions for the SIB and ADCS-ADL19, nonparametric analyses were performed; statistically significant benefit of memantine over placebo was demonstrated at week 24 for the SIB but not the ADCS-ADL19. The type and incidence of adverse events were similar in both groups.

PMID 17545739  Alzheimer Dis Assoc Disord. 2007 Apr-Jun;21(2):136-43. ・・・
著者: Frederick A Schmitt, Christopher H van Dyck, Christine H Wichems, Jason T Olin, Memantine MEM-MD-02 Study Group
雑誌名: Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):255-62. doi: 10.1097/01.wad.0000213860.35355.d4.
Abstract/Text OBJECTIVE: To investigate the cognitive effects of the N-methyl-D-aspartate receptor antagonist, memantine, with a post-hoc exploratory reanalysis of a 24-week randomized, double-blind, placebo-controlled, parallel group clinical trial comparing memantine (20 mg per day) to placebo in patients with moderate to severe Alzheimer disease (AD) receiving treatment with the cholinesterase inhibitor, donepezil.
METHODS: The effects of memantine on individual items of the Severe Impairment Battery (SIB), subscale performance, and 3 post-hoc-derived aggregate subscales were investigated. Analyses were based on the intention-to-treat population using last observation carried forward and observed cases approaches. The SIB components were assessed at baseline, weeks 4, 8, 12, 18, and 24.
RESULTS: The mean change from baseline by visit and at study end point on the SIB showed statistically significant differences between the memantine and placebo groups at all visits beginning at week 8 (last observation carried forward and observed cases). The SIB subscale analysis showed statistically significantly greater effects of memantine than placebo on memory, language, and praxis. When the SIB domains were aggregated using a face valid approach to create 3 higher-order subscales, memantine treatment resulted in statistically significant differences on memory, language, and praxis compared with placebo.
CONCLUSIONS: These post-hoc analyses support the beneficial effects of memantine on cognition observed in a previously reported clinical trial. The results presented here suggest an effect of memantine on memory, language, and praxis in patients with moderate to severe AD and support the efficacy of memantine for the treatment of cognitive deficits in AD.

PMID 17132970  Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):255-62. ・・・
著者: Howard H Feldman, Frederick A Schmitt, Jason T Olin, Memantine MEM-MD-02 Study Group
雑誌名: Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):263-8. doi: 10.1097/01.wad.0000213859.35355.59.
Abstract/Text In moderate-to-severe Alzheimer disease (AD), there are significant losses of activities of daily living (ADL). In a recent prospective, randomized, placebo-controlled trial, memantine treatment lessened the overall functional decline in AD patients already on stable donepezil therapy. In this trial, patients (n=404) with Mini-Mental State Examination scores of 5 to 14 receiving stable donepezil treatment were randomized to double-blind treatment with memantine (10 mg b.i.d.; n=203) or placebo (n=201). A primary outcome measure was the 19-item Alzheimer's Disease Cooperative Study--Activities of Daily Living Inventory (ADCS-ADL(19)). To further evaluate the treatment effects of memantine on function, we performed post hoc analyses of ADCS-ADL(19) data from this trial, including ADL items and new subscales derived from factor analysis. Using mixed model analyses, patients receiving memantine had statistically significant less decline in total ADCS-ADL(19) scores compared with placebo. An item analysis revealed statistically significant benefits of memantine on grooming, toileting, conversing, watching television, and being left alone. Statistically significant improvements were noted in subscales evaluating higher-level functions and connectedness/autonomy with memantine compared with placebo. These post hoc analyses in moderate-to-severe AD patients receiving stable donepezil treatment suggest that memantine may impact overall functional levels, and some of the cognitive processing underlying ADL performance.

PMID 17132971  Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):263-8. d・・・
著者: Pierre N Tariot, Martin R Farlow, George T Grossberg, Stephen M Graham, Scott McDonald, Ivan Gergel, Memantine Study Group
雑誌名: JAMA. 2004 Jan 21;291(3):317-24. doi: 10.1001/jama.291.3.317.
Abstract/Text CONTEXT: Memantine is a low- to moderate-affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease (AD) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed.
OBJECTIVE: To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14, who received stable doses of donepezil, conducted at 37 US sites between June 11, 2001, and June 3, 2002. A total of 322 patients (80%) completed the trial.
INTERVENTIONS: Participants were randomized to receive memantine (starting dose 5 mg/d, increased to 20 mg/d, n = 203) or placebo (n = 201) for 24 weeks.
MAIN OUTCOME MEASURES: Change from baseline on the Severe Impairment Battery (SIB), a measure of cognition, and on a modified 19-item AD Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Secondary outcomes included a Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory, and the Behavioral Rating Scale for Geriatric Patients (BGP Care Dependency Subscale).
RESULTS: The change in total mean (SE) scores favored memantine vs placebo treatment for SIB (possible score range, 0-100), 0.9 (0.67) vs -2.5 (0.69), respectively (P<.001); ADCS-ADL19 (possible score range, 0-54), -2.0 (0.50) vs -3.4 (0.51), respectively (P =.03); and the CIBIC-Plus (possible score range, 1-7), 4.41 (0.074) vs 4.66 (0.075), respectively (P =.03). All other secondary measures showed significant benefits of memantine treatment. Treatment discontinuations because of adverse events for memantine vs placebo were 15 (7.4%) vs 25 (12.4%), respectively.
CONCLUSIONS: In patients with moderate to severe AD receiving stable doses of donepezil, memantine resulted in significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior and was well tolerated. These results, together with previous studies, suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD.

PMID 14734594  JAMA. 2004 Jan 21;291(3):317-24. doi: 10.1001/jama.291.・・・
著者: Jeffrey L Cummings, Eugene Schneider, Pierre N Tariot, Stephen M Graham, Memantine MEM-MD-02 Study Group
雑誌名: Neurology. 2006 Jul 11;67(1):57-63. doi: 10.1212/01.wnl.0000223333.42368.f1.
Abstract/Text OBJECTIVE: To investigate the behavioral effects of memantine in moderate to severe Alzheimer disease (AD).
METHODS: The authors conducted a hypothesis-generating, exploratory analysis of a 24-week, double-blind, placebo-controlled trial comparing memantine (20 mg/day) with placebo in subjects with moderate to severe AD on stable donepezil treatment. They employed the Neuropsychiatric Inventory (NPI; 12-item), administered at baseline, week 12, and week 24, to assess the effects of memantine on behavior. Global, cognitive, and functional measures were collected and relationships between these assessments and changes in behavior were determined. The intent-to-treat population was examined using last-observation-carried-forward and observed-cases approaches.
RESULTS: Patients treated with memantine had significantly lower NPI total scores than patients treated with placebo. Analyses of the 12 NPI domains revealed significant effects in favor of memantine on agitation/aggression, eating/appetite, and irritability/lability. Of patients who exhibited agitation/aggression at baseline, those treated with memantine showed significant reduction of symptoms compared with placebo-treated patients. Memantine-treated patients without agitation/aggression at baseline evidenced significantly less emergence of this symptom compared with similar patients receiving placebo. Caregivers of patients receiving memantine registered significantly less agitation-related distress. There were significant relationships between the NPI and the global rating scale and performance of activities of daily living, but not between changes in the NPI and cognition.
CONCLUSION: Treatment with memantine reduced agitation/aggression, irritability, and appetite/eating disturbances. Memantine reduced agitation/aggression in patients who were agitated at baseline and delayed its emergence in those who were free of agitation at baseline.

PMID 16832078  Neurology. 2006 Jul 11;67(1):57-63. doi: 10.1212/01.wnl・・・
著者: O L Lopez, J T Becker, A S Wahed, J Saxton, R A Sweet, D A Wolk, W Klunk, S T Dekosky
雑誌名: J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):600-7. doi: 10.1136/jnnp.2008.158964. Epub 2009 Feb 9.
Abstract/Text BACKGROUND: Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects of memantine in combination with ChEIs use in Alzheimer disease (AD). This study was conducted to examine the effects of ChEIs and memantine on time to death and time to NH admission.
METHODS: Time to NH admission and death was examined in 943 probable AD patients who had at least a 1-year follow-up evaluation. Of these patients, 140 (14.9%) used both ChEIs and memantine, 387 (41%) [corrected] used only ChEIs, and 416 (44.1%) [corrected] used neither. The mean (SD) follow-up time was 62.3 (35.8) months. The analysis was conducted with multivariable Cox proportional hazard models controlling for critical covariates (ie, age, education level, gender, severity of the dementia, hypertension, diabetes mellitus, heart disease, psychiatric symptoms and use of psychotropic medications).
RESULTS: Compared with those who never used cognitive enhancers, patients who used ChEIs had a significant delay in NH admission (HR: 0.37, 95% CI 0.27 to 0.49); this effect was significantly augmented with the addition of memantine (HR: 0.29, 95% CI 0.11 to 0.72) (memantine+ChEI vs ChEI alone). ChEIs alone, or in combination with memantine had no significant association on time to death.
CONCLUSIONS: This observational study revealed that the addition of the NMDA receptor antagonist memantine to the treatment of AD with ChEI significantly altered the treated history of AD by extending time to nursing home admission.

PMID 19204022  J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):600-7. do・・・
著者: Kate McKeage
雑誌名: CNS Drugs. 2009 Oct;23(10):881-97. doi: 10.2165/11201020-000000000-00000.
Abstract/Text Memantine is an uncompetitive, moderate-affinity NMDA receptor antagonist that is indicated for the treatment of moderate to severe Alzheimer's disease. In well designed trials in patients with moderate to severe Alzheimer's disease, oral memantine monotherapy improved outcomes in the area of functional ability more than placebo in one trial, but in a second trial, treatment differences did not reach significance. Memantine has a distinct mode of action compared with that of acetylcholinesterase (AChE) inhibitors, and in a well designed study, combination therapy with memantine plus donepezil improved outcomes more than donepezil plus placebo in all four domains (function, cognition, behaviour and global change). Memantine is generally well tolerated, with adverse events occurring with a similar incidence to that reported with placebo. In modelled cost-effectiveness analyses, memantine was dominant to no therapy in regard to cost per quality-adjusted life-year (QALY) gained, and the combination of memantine plus donepezil was dominant to donepezil therapy alone in regard to QALYs gained when treatment periods exceeded 1 year in patients with moderate to severe disease. Thus, in the management of patients with moderate to severe Alzheimer's disease, memantine provides an effective treatment option. To date, clinical trial support is greater for memantine use in combination with an AChE inhibitor, while more data are needed to confirm its efficacy as monotherapy.

PMID 19739697  CNS Drugs. 2009 Oct;23(10):881-97. doi: 10.2165/1120102・・・
著者: Akira Homma, Yukimichi Imai, Hisao Tago, Takashi Asada, Masahiro Shigeta, Toshihiko Iwamoto, Masashi Takita, Itaru Arimoto, Hiroshi Koma, Takao Takase, Toshio Ohbayashi
雑誌名: Dement Geriatr Cogn Disord. 2009;27(3):232-9. doi: 10.1159/000203887. Epub 2009 Feb 25.
Abstract/Text BACKGROUND/AIMS: A 6-month, randomized, double-blind, placebo-controlled study was extended to evaluate long-term safety and efficacy of donepezil in community-dwelling Japanese patients with severe Alzheimer's disease (AD).
METHODS: 189 patients were enrolled from the double-blind study into a 52-week, open-label extension study. After a 2- to 8-week washout, donepezil was escalated within 6 weeks to 10 mg/day. Main outcomes were Severe Impairment Battery (SIB), Alzheimer's Disease Cooperative Study-Activities of Daily Living scale for severe AD (ADCS-ADL-sev) and Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). Safety parameters were monitored throughout.
RESULTS: Overall, mean change from extension study baseline in SIB scores improved until week 24; however, scores were influenced by prior treatment during the double-blind study and by length of washout. Patients treated with donepezil retained some treatment benefits after a washout of 2-4 weeks but lost all treatment benefits after a washout of 4-8 weeks. There was no change in ADCS-ADL-sev or BEHAVE-AD scores. Adverse events were consistent with the known donepezil safety profile.
CONCLUSION: Donepezil is effective and safe for symptomatic treatment of severe AD for at least 1 year. Patients who receive donepezil 10 mg daily with little or no interruption achieve the best long-term outcome.

Copyright 2009 S. Karger AG, Basel.
PMID 19246907  Dement Geriatr Cogn Disord. 2009;27(3):232-9. doi: 10.1・・・
著者: Serge Gauthier, Murat Emre, Martin R Farlow, Roger Bullock, George T Grossberg, Steven G Potkin
雑誌名: Curr Med Res Opin. 2003;19(8):707-14. doi: 10.1185/030079903125002450.
Abstract/Text Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.

PMID 14687441  Curr Med Res Opin. 2003;19(8):707-14. doi: 10.1185/0300・・・
著者: Keith Edwards, Judy Therriault O'connor, Carol Gorman
雑誌名: J Am Geriatr Soc. 2004 Nov;52(11):1965. doi: 10.1111/j.1532-5415.2004.52529_3.x.
Abstract/Text
PMID 15507085  J Am Geriatr Soc. 2004 Nov;52(11):1965. doi: 10.1111/j.・・・
著者: S Auriacombe, J J Pere, Y Loria-Kanza, B Vellas
雑誌名: Curr Med Res Opin. 2002;18(3):129-38. doi: 10.1185/030079902125000471.
Abstract/Text BACKGROUND: Selective acetylcholinesterase (AChE) and dual acetyl- and butyrylcholinesterase inhibitors constitute the only approved agents for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is a specific, reversible inhibitor of AChE, while rivastigmine is a slowly reversible (pseudoirreversible) dual cholinesterase (ChE) inhibitor, with brain-regional specificity for the cerebral cortex and hippocampus. According to the European Marketing Authorisations, the clinical benefit of ChE inhibitors should be reassessed on a regular basis and discontinuation should be considered when evidence of a therapeutic effect is no longer present. However, substantial differences in the pharmacological and pharmacokinetic profiles of the available ChE inhibitors suggest that it may be desirable to switch between ChE inhibitors if patients fail to show efficacy, deteriorate or are unable to tolerate their initially prescribed medication.
DESIGN: This open-label, six-month study evaluated the efficacy and safety of rivastigmine in 382 AD patients who had previously failed to benefit from treatment with donepezil (80% due to lack of efficacy, 11% due to tolerability problems, 9% both reasons).
RESULTS: At the end of the study, 56.2% of patients were responders to rivastigmine, as assessed using a global function scale (the Clinicians' Global Impression of Change). Cognitive performance (measured by the Mini-Mental State Examination) and the ability to perform activities of daily living (measured by the Instrumental Activities of Daily Living scale) were improved/stabilised in 48.9% and 57.0% of patients, respectively. Rivastigmine was generally well tolerated, the most common adverse events being nausea and vomiting, consistent with reports from previous clinical studies. The occurrence of side-effects or lack of efficacy with donepezil treatment was not a predictor of similar problems when treated with rivastigmine.
CONCLUSION: Rivastigmine treatment appears to be beneficial in AD patients who have previously failed to benefit from, or were unable to tolerate treatment with, donepezil.

PMID 12094822  Curr Med Res Opin. 2002;18(3):129-38. doi: 10.1185/0300・・・
著者: L Bartorelli, C Giraldi, M Saccardo, S Cammarata, G Bottini, A M Fasanaro, A Trequattrini, Upgrade Study Group
雑誌名: Curr Med Res Opin. 2005 Nov;21(11):1809-18. doi: 10.1185/030079905X65655.
Abstract/Text OBJECTIVE: Cholinesterase (ChE) inhibitors are the only medications approved for the treatment of Alzheimer's disease (AD). The features of ChE inhibitors differ considerably. In addition to acetylcholinesterase (AChE) inhibition, rivastigmine also inhibits butrylcholinesterase (BuChE), providing dual AChE and BuChE inhibition. An observational study was performed to determine the response in routine clinical practice to switching AD patients to rivastigmine from a selective AChE inhibitor when that treatment no longer delivered a satisfactory clinical response.
RESEARCH DESIGN AND METHODS: A prospective, multicentre, 3-month observational trial in patients with mild to moderately severe AD (adjusted Mini Mental State Examination [MMSE] score 10-26) deteriorating (at least 2 adjusted MMSE points in last 6 months) on selective AChE inhibitor treatment. Adjusted MMSE, activities of daily living (ADL) and instrumental activities of daily living (IADL), the Zarit caregiver burden and global function (short Clinical Global Impression of Change, CGIC) scores were noted before the switch and 3 months after the switch.
RESULTS: 225 patients entered the study. The switches made were from donepezil to rivastigmine in (D-R) in 188 patients, galantamine to rivastigmine (G-R) in 33 patients and donepezil to galantamine (D-G) in four patients. Ten patients discontinued due to adverse events and eight for other reasons. More than half of the switches were within 36 hours of a patient's first treatment visit. In the D-R and G-R groups, 67.7% and 66.7% of patients responded (CGIC score < or = 4), respectively. In non-responders, worsening (CGIC score 5-7) was mild in approximately 80% or more of patients. Adjusted MMSE improved after the switch from both donepezil and galantamine to rivastigmine (+0.69 +/- 3.2, p = 0.008 and +0.6 +/- 1.6, p = 0.05, respectively). Mean ADL, IADL, and Zarit scores remained stable. The proportion of patients on concomitant antipsychotic therapy diminished by 30.5% and benzodiazepines were discontinued in all patients, except one.
CONCLUSIONS: AD patients deteriorating on selective AChE inhibitor treatment can benefit from switching to a dual AChE-BuChE inhibitor, such as rivastigmine, in terms of stabilization of disease, improvement in cognitive function and reduction in the burden of concomitant psychoactive treatment. The switch was well tolerated. Confirmation of these results is required in a controlled study.

PMID 16307702  Curr Med Res Opin. 2005 Nov;21(11):1809-18. doi: 10.118・・・
著者: Jeffrey Cummings, Bengt Winblad
雑誌名: Expert Rev Neurother. 2007 Nov;7(11):1457-63. doi: 10.1586/14737175.7.11.1457.
Abstract/Text Rivastigmine patch is the first transdermal treatment to be approved for Alzheimer's disease (AD) and Parkinson's disease dementia in the USA and for AD in Europe. It provides smooth, continuous drug delivery, and has the potential to maintain rivastigmine concentrations within an optimal therapeutic window while avoiding the peaks and troughs associated with oral drug delivery. The target dose, rivastigmine 9.5 mg/24 h patch (a 10 cm(2) patch), is given once daily and requires a simple one-step dose titration to the therapeutic dose. In a 24-week study in 1195 AD patients, the rivastigmine 9.5 mg/24 h patch provided similar efficacy to the highest dose range of capsules, with approximately three-times fewer reports of nausea and vomiting. Patients in the 9.5 mg/24 h patch and 12 mg/day capsule groups evidenced significant improvements versus placebo on both primary outcome measures: the Alzheimer's Disease Assessment Scale-Cognitive subscale; and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change; in addition to the following secondary outcome measures: Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Mini-Mental State Examination; and Trail Making Test Part A for assessment of attention, visual tracking and motor processing speed. Treatment differences on the Neuropsychiatric Inventory and Ten Point Clock-drawing Test did not reach statistical significance in this study. The patch may be the optimal way to treat dementia patients with rivastigmine.

PMID 17997695  Expert Rev Neurother. 2007 Nov;7(11):1457-63. doi: 10.1・・・
著者: L Clare, R T Woods, E D Moniz Cook, M Orrell, A Spector
雑誌名: Cochrane Database Syst Rev. 2003;(4):CD003260. doi: 10.1002/14651858.CD003260.
Abstract/Text BACKGROUND: Memory problems are a defining feature of the early stages of Alzheimer's disease (AD) and vascular dementia. Cognitive training and cognitive rehabilitation are specific approaches designed to address everyday memory difficulties.
OBJECTIVES: The main aim was to evaluate the effectiveness and impact of cognitive training and cognitive rehabilitation interventions aimed at improving memory functioning for people in the early stages of Alzheimer's disease or vascular dementia. The two types of intervention were considered separately.
SEARCH STRATEGY: The CDCIG Specialized Register, which contains records from MEDLINE, EMBASE, CINAHL, PsycINFO and many other databases, was searched on 9 April 2003.
SELECTION CRITERIA: RCTs comparing cognitive rehabilitation or cognitive training interventions with comparison conditions, and reporting outcomes for the person with dementia and/or the family caregiver, were considered for inclusion.
DATA COLLECTION AND ANALYSIS: Six studies reporting cognitive training interventions were included. Statistical analyses were conducted to provide an indication of intervention effect sizes. Data from ordinal scales was treated as continuous, and a fixed effects model was applied in calculating weighted mean differences and 95% confidence intervals. No studies were found that reported a fully individualised cognitive rehabilitation approach.
MAIN RESULTS: None of the six studies reporting cognitive training interventions demonstrated any statistically significant effects in any domain, although there were indications of some modest, non-significant effects in various domains of cognitive functioning.
REVIEWER'S CONCLUSIONS: The present findings do not provide strong support for the use of cognitive training interventions for people with early-stage AD or vascular dementia, although these findings must be viewed with caution due to the limited number of RCTs available and to the methodological limitations identified, and further well-designed trials would help to provide more definitive evidence. Due to a complete absence of RCTs evaluating an individualised cognitive rehabilitation approach, It is not possible at present to draw conclusions about the efficacy of individualised cognitive rehabilitation interventions for people with early-stage dementia, and further research is required in this area.

PMID 14583963  Cochrane Database Syst Rev. 2003;(4):CD003260. doi: 10.・・・
著者: A Spector, M Orrell, S Davies, B Woods
雑誌名: Cochrane Database Syst Rev. 2000;(4):CD001119. doi: 10.1002/14651858.CD001119.
Abstract/Text BACKGROUND: Reality Orientation (RO) was first described as a technique to improve the quality of life of confused elderly people, although its origins lie in an attempt to rehabilitate severely disturbed war veterans, not in geriatric work. It operates through the presentation of orientation information (eg time, place and person-related) which is thought to provide the person with a greater understanding of their surroundings, possibly resulting in an improved sense of control and self-esteem. There has been criticism of RO in clinical practice, with some fear that it has been applied in a mechanical fashion and has been insensitive to the needs of the individual. There is also a suggestion that constant relearning of material can actually contribute to mood and self-esteem problems. There is often little consistent application of psychological therapies in dementia services, so a systematic review of the available evidence is important in order to identify the effectiveness of the different therapies. Subsequently, guidelines for their use can be made on a sound evidence base.
OBJECTIVES: To assess the evidence of effectiveness for the use of Reality Orientation (RO) as a classroom-based therapy on elderly persons with dementia.
SEARCH STRATEGY: Computerised databases were searched independently by 2 reviewers entering the terms 'Reality Orientation, dementia, control, trial or study'. Relevant web sites were searched and some hand searching was conducted by the reviewer. Specialists in the field were approached for undocumented material, and all publications found were searched for additional references.
SELECTION CRITERIA: All randomised controlled trials (RCTs), and all controlled trials with some degree of concealment, blinding or control for bias (second order evidence) of Reality Orientation as an intervention for dementia were included. The criteria for inclusion/exclusion involved systematic assessment of the quality of study design and the risk of bias, using a standard data extraction form. A measure of cognitive and/or behavioural change was needed.
DATA COLLECTION AND ANALYSIS: Data were extracted independently by both reviewers, using a previously tested data extraction form. Authors were contacted for data not provided in the papers. Psychological scales measuring cognitive and behavioural changes were examined.
MAIN RESULTS: 6 RCTs were entered in the analysis, with a total of 125 subjects (67 in experimental groups, 58 in control groups). Results were divided into 2 subsections: cognition and behaviour. Change in cognitive and behavioural outcomes showed a significant effect in favour of treatment.
REVIEWER'S CONCLUSIONS: There is some evidence that RO has benefits on both cognition and behaviour for dementia sufferers. Further research could examine which features of RO are particularly effective. It is unclear how far the benefits of RO extend after the end of treatment, but and it appears that a continued programme may be needed to sustain potential benefits.

PMID 11034699  Cochrane Database Syst Rev. 2000;(4):CD001119. doi: 10.・・・
著者: Aimee Spector, Lene Thorgrimsen, Bob Woods, Lindsay Royan, Steve Davies, Margaret Butterworth, Martin Orrell
雑誌名: Br J Psychiatry. 2003 Sep;183:248-54.
Abstract/Text BACKGROUND: A recent Cochrane review of reality orientation therapy identified the need for large, well-designed, multi-centre trials.
AIMS: To test the hypothesis that cognitive stimulation therapy (CST) for older people with dementia would benefit cognition and quality of life.
METHOD: A single-blind, multi-centre, randomised controlled trial recruited 201 older people with dementia. The main outcome measures were change in cognitive function and quality of life. An intention-to-treat analysis used analysis of covariance to control for potential variability in baseline measures.
RESULTS: One hundred and fifteen people were randomised within centres to the intervention group and 86 to the control group. At follow-up the intervention group had significantly improved relative to the control group on the Mini-Mental State Examination (P=0.044), the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) (P=0.014) and Quality of Life - Alzheimer's Disease scales (P=0.028). Using criteria of 4 points or more improvement on the ADAS-Cog the number needed to treat was 6 for the intervention group.
CONCLUSION: The results compare favourably with trials of drugs for dementia. CST groups may have worthwhile benefits for many people with dementia.

PMID 12948999  Br J Psychiatry. 2003 Sep;183:248-54.
著者: Patricia Heyn, Beatriz C Abreu, Kenneth J Ottenbacher
雑誌名: Arch Phys Med Rehabil. 2004 Oct;85(10):1694-704.
Abstract/Text OBJECTIVE: To determine by meta-analysis whether physical exercises are beneficial for people with dementia and related cognitive impairments.
DATA SOURCES: Published articles and nonpublished manuscripts from 1970 to 2003 were identified by using electronic and manual searches. Key search words included exercise, rehabilitation, activities of daily living, dementia, Alzheimer's disease, aged, and geriatrics.
STUDY SELECTION: Reviewed studies were limited to randomized trials evaluating exercise in persons 65 years of age or older with cognitive impairment. Studies included quantitative results (means, standard deviations, t tests, F tests) for physical fitness, physical functioning, cognition, or behavior outcomes.
DATA EXTRACTION: One reviewer extracted data on study characteristics and findings. Selected articles were evaluated for methodologic quality by 2 raters.
DATA SYNTHESIS: A total of 2020 subjects participated in the 30 trials that met the inclusion criteria. Summary effects were computed using a fixed effects (Hedge's g(i)) model. Significant summary effect sizes (ES) were found for strength (ES=.75; 95% confidence interval [CI], .58-.92), physical fitness (ES=.69; 95% CI, .58-.80), functional performance (ES=.59; 95% CI, .43-.76), cognitive performance (ES=.57; 95% CI, 0.43-1.17), and behavior (ES=.54; 95% CI, .36-.72). The overall mean ES between exercise and nonexercise groups for all outcomes was .62 (95% CI, .55-.70).
CONCLUSIONS: Exercise training increases fitness, physical function, cognitive function, and positive behavior in people with dementia and related cognitive impairments.

PMID 15468033  Arch Phys Med Rehabil. 2004 Oct;85(10):1694-704.
著者: Stanley Colcombe, Arthur F Kramer
雑誌名: Psychol Sci. 2003 Mar;14(2):125-30.
Abstract/Text A meta-analytic study was conducted to examine the hypothesis that aerobic fitness training enhances the cognitive vitality of healthy but sedentary older adults. Eighteen intervention studies published between 1966 and 2001 were entered into the analysis. Several theoretically and practically important results were obtained. Most important fitness training was found to have robust but selective benefits for cognition, with the largest fitness-induced benefits occurring for executive-control processes. The magnitude of fitness effects on cognition was also moderated by a number of programmatic and methodological factors, including the length of the fitness-training intervention, the type of the intervention, the duration of training sessions, and the gender of the study participants. The results are discussed in terms of recent neuroscientific and psychological data that indicate cognitive and neural plasticity is maintained throughout the life span.

PMID 12661673  Psychol Sci. 2003 Mar;14(2):125-30.
著者: O Zanetti, G Binetti, E Magni, L Rozzini, A Bianchetti, M Trabucchi
雑誌名: Acta Neurol Scand. 1997 Mar;95(3):152-7.
Abstract/Text The study evaluates the efficacy of a procedural memory stimulation programme in mild and mild-moderate Alzheimer's disease (AD). Twenty basic and instrumental activities of daily living have been selected, and divided into two groups, comparable for difficulty. Ten normal elderly subjects (age 68.0 +/- 4.8 years; MMSE score: 28.7 +/- 0.9; education: 7.6 +/- 3.5 years) were asked to perform the two groups of daily activities and the time required to perform the tasks of each group was recorded and used as a reference. Ten mild and mild-moderate AD patients (age 77.2 +/- 5.3 years; MMSE score: 19.8 +/- 3.5; education: 7.3 +/- 4.7 years) without major behavioural disturbances constituted the experimental group. Patients were evaluated in all 20 daily activities and the time employed was recorded at baseline and after a 3-week training (1 h/d, 5 d/week) period. Five patients were trained during the 3 weeks on half of the 20 daily activities and the other five patients were trained on the remainder. This procedure was adopted in order to detect separately the improvement in "trained" and "not trained" activities, allowing to control better the effects of the intervention. The assessment of the functional impact of the training was directly measured, through the variation of time employed to perform tasks before and after training. After 3 weeks of training a significant improvement was observed for the trained activities, from 3.6 to 1.9 standard deviations below the performance of the normal elderly controls (P < 0.05). AD patients improved also in not-trained activities from 3.5 to 2.7 standard deviations below the controls' performance (P < 0.05). The rehabilitation of activities of daily living through developing procedural memory strategies may be effective in mild and mild-moderate AD patients.

PMID 9088383  Acta Neurol Scand. 1997 Mar;95(3):152-7.
著者: Elisabetta Farina, R Fioravanti, L Chiavari, E Imbornone, M Alberoni, S Pomati, G Pinardi, R Pignatti, C Mariani
雑誌名: Acta Neurol Scand. 2002 May;105(5):365-71.
Abstract/Text OBJECTIVES: To evaluate the efficacy of two different procedures of individual cognitive training in mild to moderate Alzheimer's Disease (AD).
MATERIAL AND METHODS: Twenty-two AD patients entered the study. We compared stimulation of procedural memory (group 1) with training of partially spared cognitive functions (group 2). Assessment included: neuropsychological tests, scales, and the Functional Living Skills Assessment (FLSA), a standardized battery built to directly evaluate patients' performance in everyday life.
RESULTS: We observed a significant improvement for both groups after training in FLSA total score (P=0.005) and subscales. For group 1, we also found a slightly improved performance in two tests: Attentional Matrices (P=0.041), and Verbal Fluency for Letters (P=0.059). After 3 months, patients' results showed a tendency to regress to the pre-training level.
CONCLUSION: Both AD groups showed a substantial improvement after training in a direct performance measure of everyday functioning. However, results at neuropsychological tests suggest that training activities of daily living (supported by procedural memory) may be more effective than stimulating "residual" cognitive functions.

PMID 11982487  Acta Neurol Scand. 2002 May;105(5):365-71.
著者: R N Davis, P J Massman, R S Doody
雑誌名: Alzheimer Dis Assoc Disord. 2001 Jan-Mar;15(1):1-9.
Abstract/Text The efficacy of a cognitive intervention consisting of training in face-name associations, spaced retrieval, and cognitive stimulation was tested in a sample of 37 patients (16 men, 21 women) with probable Alzheimer disease (AD). Patients with AD were randomly assigned to receive either the cognitive intervention or a mock (placebo) intervention for 5 weeks. The placebo group then crossed over to receive the intervention. During the intervention, AD patients showed significant improvement in recall of personal information, face-name recall, and performance on the Verbal Series Attention Test. Improvement did not generalize to additional neuropsychologic measures of dementia severity, verbal memory, visual memory, word generation, or motor speed, or to caregiver-assessed patient quality of life. Results suggest that although face-name training, spaced retrieval, and cognitive stimulation may produce small gains in learning personal information and on a measure of attention, improvement does not generalize to overall neuropsychologic functioning or patient quality of life.

PMID 11236819  Alzheimer Dis Assoc Disord. 2001 Jan-Mar;15(1):1-9.
著者: L Bäckman
雑誌名: Acta Neurol Scand Suppl. 1992;139:84-9.
Abstract/Text
PMID 1414274  Acta Neurol Scand Suppl. 1992;139:84-9.
著者: M P Quayhagen, M Quayhagen
雑誌名: Gerontologist. 1989 Apr;29(2):150-5.
Abstract/Text Assessed was the efficacy of a home-based program of cognitive stimulation for the functional status of patients with Alzheimer's disease, as well as the well-being of caregivers. Ten family dyads (caregiver and patient) participated in the intervention and six family dyads formed the comparison group. Patients in the program maintained their levels of cognitive and behavioral functioning while improving emotionally, whereas the comparison group patients deteriorated. Similarly, the caregivers in the program maintained well-being and enhanced their coping resources.

PMID 2666277  Gerontologist. 1989 Apr;29(2):150-5.
著者: M P Quayhagen, M Quayhagen, R R Corbeil, P A Roth, J A Rodgers
雑誌名: Nurs Res. 1995 May-Jun;44(3):153-9.
Abstract/Text A cognitive remediation intervention was tested for its effect on functional outcomes of older care recipients with the diagnosis of dementia of the Alzheimer's type. The 78 community-dwelling care recipients were assessed on cognitive and behavioral functioning and randomly assigned to one of three conditions. Care recipients were expected to benefit most from active cognitive stimulation training as compared to placebo (passive) activity or wait-list control conditions. Following each weekly instruction session, the intervention was executed in the home by the family caregiver. Care recipients in the experimental group improved in cognitive and behavioral performance with treatment, but returned to former level of functioning by the 9th month. In contrast, the control group declined, while the placebo group remained static on these variables. These findings support the viability of remediation interventions in dementia despite the trajectory of cognitive decline.

PMID 7761291  Nurs Res. 1995 May-Jun;44(3):153-9.
著者: R N BUTLER
雑誌名: Psychiatry. 1963 Feb;26:65-76.
Abstract/Text
PMID 14017386  Psychiatry. 1963 Feb;26:65-76.

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