今日の臨床サポート

レビー小体型認知症

著者: 梁正淵 北里大学 北里研究所病院 脳神経内科

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正済:2021/09/15
現在監修レビュー中
参考ガイドライン:
  1. Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium. Neurology 2017 Jul 4 89(1);88-100.
  1. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 2020 Apr 25 94(17) 743-755.
患者向け説明資料

概要・推奨   

  1. いかに早期に診断し、早期の疾病介入ができるか ということは、『軽度認知症』という概念をはじめ、アルツハイマー病(型認知症)やパーキンソン病をはじめとしたレビー小体病における自律神経障害、嗅覚障害、REM睡眠行動障害などの合併が、認知機能障害やパーキンソン症状の出現前にも観察されうる症例があり、これらの症状を確認した場合には、今回、“prodromal”という言葉が使われているように、中核症状がなくともその後の経過に注視していくことが大切である。
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:
梁正淵 : 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. 臨床診断に関して大きな変更はないが、いかに早期に診断し、早期介入ができるか ということが変性性認知機能障害性神経変性疾患においても注目されており、中核症状のみならず、他の症状出現・確認時には注意深い経過観察が大切である。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. レビー小体型認知症は進行性の認知機能障害を呈するときに疑われる疾患である。
  1. 高齢者の認知機能障害を来す疾患ではアルツハイマー型認知症に次いで多い変性性認知機能障害疾患といわれている。
  1. 物忘れが主体となるアルツハイマー型認知症に対して幻覚、特に幻視、妄想などの認知症に伴う行動・心理症状behavioral and psychological symptoms of dementia(BPSD)が前景になることがしばしば見受けられることが特徴であり、これらは患者や介護者の日常生活における負担を増大しQOL低下の原因となることが多いため、早期に、的確に当疾患を診断し患者・家族に疾患をご理解していただき、適切な時期に適切な治療を開始することが望まれる。ときとしてパーキンソン症状、錐体外路症状、運動機能障害も合併し、さらなるQOL低下の要因となり、この場合はパーキンソン症状の治療も重要である。
  1. 中核症状のみならず、他の症状(支持的臨床症状)確認時には、その後の経過を注意深く観察することが大切である。
 
レビー小体

a:黒質;HE染色。
b:黒質;抗α-synuclein抗体を用いた免疫染色でのレビー小体とα-synuclein陽性neurites (Lewy neuritisと表現されることもある)。
c:大脳皮質;HE染色。
d:大脳皮質;抗α-synuclein抗体を用いた免疫染色でのレビー小体。

出典

 
  1. レビー小体型認知症に関して(推奨度1G)
  1. レビー小体型認知症は1961年に岡崎春雄とLewis E Lipkinによる症例報告[1]に始まるが、当疾患が大きく注目されたのは1976年よりの小阪らの一連の報告による[2][3][4][5][6][7]。彼は1990年までにLewy body disease、diffuse Lewy body diseaseという疾患名で当疾患を体系づくった。
  1. この一連の報告のなかで、レビー小体病という概念から神経病理学的に3群に分類した。間脳・脳幹にはレビー小体が多数存在するが、大脳皮質や基底核にはほとんどみられない一群。大脳皮質・基底核・間脳・脳幹に広範に多数出現する一群。この2群の中間的に間脳・脳幹に多数出現し、大脳皮質・基底核にも散在する一群。この3群で間脳・脳幹にレビー小体が限局する一群がパーキンソン病とし、大脳皮質・基底核・間脳・脳幹に広範に多数出現する一群をびまん性レビー小体病と提唱した(1996年には黒質にはわずかなレビー小体の出現にもかかわらず、大脳皮質に多数のレビー小体の出現を認める症例をレビー小体病の第4のタイプとして報告している)。
  1. その後アルツハイマー型認知症の病理変化の合併をもとにcommon formとpure formに分類し、それぞれの群での臨床的特徴をまとめた。common formは病理学的に多少ともアルツハイマー型認知症の病理像を合併し、臨床的には初老期、老年期に、60%は認知機能障害で発症し、25%はパーキンソン症状や自律神経症状から発症した。30%弱には終生パーキンソン症状の出現はみなかった。pure formは病理学的にはアルツハイマー型認知症の病理学的変化が乏しく、パーキンソン症状に進行性の認知機能障害が合併する群と定義づけた。
  1. このような報告があって、1990年 RH Perryらはsenile dementia of Lewy body type[8]、L HansenらはLewy body variant of Alzheimer’s disease[9]という疾患名で同様の、類似の一群を報告した。そこで1995年Ian G McKeithらが中心となりNewcastle upon Tyne, UKで『The 1st International Workshop Dementia with Lewy Bodies』が開催され、dementia with Lewy bodies(DLB)という疾患用語・疾患単位が提唱され、第1版の臨床、病理におけるガイドラインが示された[10]。このガイドラインには小阪の報告内容が随所に取り入れられている。
  1. 以降、この診断基準の妥当性、信憑(頼)性に関して感度、特異度における報告がさまざまなグループよりなされ、2003年9月に『The 3rd International Workshop on Dementia with Lewy bodies and Parkinson’s disease dementia』が、再びNewcastle upon Tyne, UKで開催され、2005年改訂版の臨床診断基準が発表された[11]
  1. 2015年12月にフロリダで『International Dementia with Lewy Bodies Conferebce』が開催され、2017年に『Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium.』として Neurology 2017 Jul 4 89(1);88-100[12]に掲載された。変更点は、臨床的特徴と各種検査項目が『バイオマーカー』として区別・確立され、『中核的症状』と『バイオマーカー』の組み合わせで『Probable』『Possible』に診断する形式になった。臨床症状では『レム睡眠行動障害』が、諸検査項目『バイオマーカー』では『MIBG心筋シンチ』が診断における比重が高められた。
  1. 原文中、『Clinical features』の項目で、認知機能障害に対する心理検査で具体的な検査が示され、施行を推奨しており、これは、内容的にはDSM-5の改訂に準じたものと思われる。また、『Core clinical features.(中核的臨床症状)』の『Fluctuation.(変動)』や『Visual hallucinations.(幻視)』においてもスケールを用いてのスコア化を推奨しているのは同様である。『Parkinsonism.(パーキンソニズム)』では無動、安静時振戦、固縮のいずれか一つのみでも記載を必須としている。
  1. 『Supportive clinical features.(支持的臨床症状)』では、新たなものとして過眠と嗅覚障害を取り上げている。これは、国内においてもパーキンソン病や認知機能障害性疾患において話題になっていることは周知のごとくである。
  1. この『Supportive clinical features.(支持的臨床症状)』には、『重度の自律神経障害、例えば、便秘、起立性低血圧、尿失禁』が記載されている。自律神経障害に関しては前改訂(Neurology 2005 Dec 27 65(12) 1863-1872.)から記載された項目であるが、Pure autonomic failure (PAF)という観点から2017年にThe Autonomic Disorders Consortiumからは前方視的に、Mayo Clinicから後方視的の報告がされている[13][14]。それぞれ、結果は異なるものの、DLBにおいても自律神経障害は重要な症状発症前のマーカーになりうることが指摘されている。
  1. 今回は、2019年6月に米国ネバダ州ラスベガスで開催された国際レビー小体型認知症会議(The International Lewy Body Dementia Conference)が開催され、その後のリヴューを含めた報告が、『Research criteria for the diagnosis of prodromal dementia with Lewy bodiesという表題でNeurology 2020 Apr 25 94(17)[15]に掲載された。アルツハイマー病やパーキンソン病に代表される神経変性疾患、特にコンフォメーション病と呼ばれる神経変性疾患に関しては、主症状発症前にすでに異常蛋白質の沈着は始まっており、いかにこの発症段階前、前段階(“prodromal”という言葉で表現されることが多い)で診断し、早期の介入に結び付けていくか ということが大きな関心事となり、注目を集めていることが反映されていると思われる。これは、『軽度認知症』という概念や、アルツハイマー病(型認知症)やパーキンソン病をはじめとしたレビー小体病における自律神経障害、嗅覚障害、REM睡眠行動障害などの合併が、認知機能障害やパーキンソン症状の出現前にも観察されうる症例があり、これらの症状を確認した場合には中核症状がなくともその後の経過に注視していく必要がある。今回の報告は、現状ではすぐに臨床応用できるものではないとされ、研究・リサーチ段階での使用を目的としており、今回は、あえて原文で記載するので参考にしていただきたい<図表><図表><図表><図表>
  1. ここでは、レビー小体型認知症の前駆期として、1)軽度認知症、2)せん妄発症、3)精神症状発症 の3系が示されている。
  1. “prodromal”という語は、症候前認知症期(prodromal AD)という用語は2007年 NINCDS-ADRDAの研究用改訂版でAD発症以前をpreclinical AD,MCIを含む症候性認知症期をprodromal AD、明らかな認知症を呈する時期をAD dementiaとした。Prodromal ADはMCI due to ADとほとんど同義であり、Prodromal LBDに対し、(1) mild cognitive impairment(MCI)、(2) delirium-onset、(3) psychiatric-onsetの分類は混乱をきさないか心配ではあるが、大切なことは、せん妄や、精神症状に遭遇した際にはDLBを鑑別に挙げることが大切なことと思われる。
  1. 日本においては『痴呆』という用語が2004年末に『認知症』と変更が促されたと同様、DSM 5では、それまでの『dementia』という用語に変わり『neurocognitive disorders』という用語が用いられ、これは『major neurocognitive disorder』、『mild neurocognitive disorder』に分類され、『mild neurocognitive disorder』は『MCI』に相当するとされている。したがってDSM 5では『Dementia with Lewy bodies』に『Dementia』という用語は外され、『Major Neurocognitive Disorder with Lewy bodies』と記されたが、日本語は『レビー小体病を伴う認知症』と訳されている。そしてこの疾患をコーディングする際、『Note:Code first 331.82 (G31.83) Lewy body disease』とも記されている。DSM 5は『Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease』という項目も設けており、『パーキンソン病の認知症』とは区別し、DLB Consortiumと同様に『Neurocognitive Disorder with Lew bodies』とは区別する立場にある。『Major or Mild Neurocognitive Disorder Due to Parkinson’s Disease』にも疾患をコーディングする際の注意事項が記されているが、ここには、『Note:Code first 332.0 (G20) Parkinson’s disease』と記されている。
  1. ここで問題なのは、『Lewy body disease=レビー小体病』という用語の始まりは、先にも記した小阪憲司が1980年 精神神経学雑誌で『“Lewy小体病”の臨床神経病理学的研究』[4]で初めて用い、彼はLewy小体がその病態に何らかの影響を及ぼしている疾病の一群としてとらえ、脳幹中心に出現しているものがパーキンソン病、その出現が大脳皮質広範に及んでいるものが、その後命名された、『びまん性Lewy小体病;diffuse Lewy body disease/diffuse type of Lewy body disease』であり、この項目の『レビー小体認知症 Dementia with Lewy bodies』とほぼ同義とされている。『Lewy body disease=レビー小体病』にはパーキンソン病も含まれる。したがって、DSM 5のこの分類においても、また、日本語訳の『Lewy小体病に伴う認知症』となっていることも『Lewy body disease=レビー小体病』の概念に混乱をされる方もいるのではないかと危惧している。DLB ConsortiumはDLB/PDDの区別が困難な場合など、『Lewy body disease=レビー小体病』を用いることを推奨している。筆者は、『Lewy body disease=レビー小体病』という用語は、あくまでも小阪が命名したもので用いるべきと考えている。
病歴・診察のポイント  
  1. どのような認知機能障害に関係する症状の出現なのか。中核症状か、いわゆる周辺症状 BPSDか。また、それらの症状はいつから、どのようなときに出現しているのかを具体的に聞きとる。

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文献 

著者: H OKAZAKI, L E LIPKIN, S M ARONSON
雑誌名: J Neuropathol Exp Neurol. 1961 Apr;20:237-44.
Abstract/Text
PMID 13730588  J Neuropathol Exp Neurol. 1961 Apr;20:237-44.
著者: K Kosaka, S Oyanagi, M Matsushita, A Hori
雑誌名: Acta Neuropathol. 1976 Nov 15;36(3):221-33.
Abstract/Text An autopsy case of unclassifiable presenil dementia is reported. The outstanding pathological findings were as follows; 1. presence of senile plaques, neurofibrillary changes, Pick bodies, Hirano bodies, granulovacuolar degeneration of neurons, etc. 2. numerous Lewy bodies in the brain stem and diencephalon, 3. peculiar swollen neurons with intracytoplasmic, eosinophilic and argentophilic inclusions ("Lewy-like-bodies") in the cerebral cortices. Detailed study of the last mentioned inclusions indicates that they are almost identical to Lewy bodies, though there are some minor differences, in histochemical and electronmicroscopic findings. Nosologically, this case may represent either a combination of Alzheimer's disease, Pick's disease and idiopathic Parkinsonism with "Lewy-like-bodies" in the cerebral cortices, or a single disease. As far as we know, no similar case been reported.

PMID 188300  Acta Neuropathol. 1976 Nov 15;36(3):221-33.
著者: K Kosaka
雑誌名: Acta Neuropathol. 1978 May 24;42(2):127-34.
Abstract/Text The histochemical and structural properties and the topographical distribution pattern of Lewy bodies in the cerebral cortex as well as in the brain stem and diencephalon were studied in three cases. The Lewy bodies in the cerebral cortex were found in the small or medium-sized neurons of the fifth and sixth layers, particularly in the anterior frontal, temporal, insular, and cingulate cortex, and showed minor differences in their histochemical and structural properties from typical Lewy bodies in the brain stem and diencephalon. By light microscopy they were more irregular in shape, less eosinophilic, less sharply demarcated, and did not have clear halos and central cores. From the ultrastructural aspect, the filaments in them did not radiate, but were arranged at random, and circular profiles were not associated in the central zone. This type of Lewy body was also distributed in the basal ganglia. A close relationship between Lewy bodies and monoamines in the cerebral cortex of our cases was not recognized. These three cases showed also concomitant senile changes, i.e., senile plaques and neurofibrillary tangles.

PMID 654884  Acta Neuropathol. 1978 May 24;42(2):127-34.
著者: M Yoshimura
雑誌名: J Neurol. 1983;229(1):17-32.
Abstract/Text
PMID 6189974  J Neurol. 1983;229(1):17-32.
著者: K Kosaka, M Yoshimura, K Ikeda, H Budka
雑誌名: Clin Neuropathol. 1984 Sep-Oct;3(5):185-92.
Abstract/Text The term Lewy body disease (LBD) was proposed earlier to describe a disease classified into three types (A, B, and C) according to the distributional pattern of Lewy bodies in the CNS. Group A (diffuse type of LBD) shows clinical symptoms of "dementia-parkinsonism syndrome". The most remarkable pathologic feature is the widespread appearance of numerous Lewy bodies not only in the brain stem and diencephalon (as in group C), but also in the cerebral cortex and basal ganglia, which is complicated by senile changes of various degrees. Group B is the transitional type between groups A and C. Group C (brain stem type of LBD) is identical with idiopathic Parkinson's disease. In this paper, 12 of our cases with diffuse type LBD were studied clinicopathologically and compared with eight similar cases in the literature. The neuropathologic substrate of progressive dementia in this disease is also discussed. LBD is a clinicopathologic entity; the diffuse type of LBD, a special form of this disease, presents mainly a presenile dementia.

PMID 6094067  Clin Neuropathol. 1984 Sep-Oct;3(5):185-92.
著者: K Kosaka
雑誌名: J Neurol. 1990 Jun;237(3):197-204.
Abstract/Text Thirty-seven Japanese autopsy cases with diffuse Lewy body disease (DLBD) were reviewed from a clinicopathological viewpoint. Based on the neuropathological finding of whether or not many concomitant senile plaques (SPs) and/or neurofibrillary tangles (NFTs) are present. DLBD is divided into two forms: a common form and a pure form. In the common form not only numerous Lewy bodies but also many SPs and/or NFTs are found in the cerebral cortex, whereas in the pure form there are no or few senile changes. Of the 37 cases, 28 cases had the common form, and 9 had the pure form of DLBD. In the common form all cases had shown progressive cortical dementia in the presenile or senile period. About 60% of the cases began with memory disturbance, while 25% showed Parkinson's or Shy-Drager syndrome initially. Parkinson's syndrome, consisting mainly of muscular rigidity and akinesia, was usually marked in the later stage, although there were also 8 cases (28.6%) in which no parkinsonian symptoms were detected even in the terminal stage. On the other hand, almost all cases with the pure form of DLBD showed juvenile Parkinson's syndrome, followed by progressive cortical dementia, although there was one presenile case with mild dementia and Parkinson's syndrome. These Japanese cases are compared with cases reported in Western countries.

PMID 2196340  J Neurol. 1990 Jun;237(3):197-204.
著者: R H Perry, D Irving, G Blessed, A Fairbairn, E K Perry
雑誌名: J Neurol Sci. 1990 Feb;95(2):119-39.
Abstract/Text A dementing syndrome has been identified in a group of psychiatric cases aged 71-90 years, presenting initially with a subacute/acute confusional state, often fluctuating and associated with visual hallucinations and behavioural disturbances. Clinically, these cases did not meet criteria for a diagnosis of Alzheimer's disease, and many were assigned to the multiinfarct dementia group, although no significant ischaemic lesions were evident at autopsy. Mild extrapyramidal features were apparent in a number of cases but the characteristic clinical triad of Parkinson's disease, i.e., tremor, rigidity, and akinesia, was absent. Detailed neuropathological examination revealed Lewy body formation and selective neuronal loss in brain stem and other subcortical nuclei, accompanied by Lewy body formation in neo- and limbic cortex, at densities well below those previously reported in diffuse Lewy body disease. A variable degree of senile degenerative change was present; numerous senile plaques and minimal neurofibrillary tangles in most cases. Neither the clinical nor the neuropathological features of this group are typical of Parkinson's or Alzheimer's disease, but suggest a distinct neurodegenerative disorder, part of the Lewy body disease spectrum, in which mental symptoms predominate over motor disabilities and lead to eventual psychogeriatric hospital admission. In a sequential series of autopsies conducted on clinically assessed demented patients, neuropathological analysis has indicated that such cases may comprise up to 20% of a hospitalized population of demented old people over the age of 70 years, an observation clearly relevant to the diagnosis and management of dementia in the elderly.

PMID 2157823  J Neurol Sci. 1990 Feb;95(2):119-39.
著者: L Hansen, D Salmon, D Galasko, E Masliah, R Katzman, R DeTeresa, L Thal, M M Pay, R Hofstetter, M Klauber
雑誌名: Neurology. 1990 Jan;40(1):1-8.
Abstract/Text Thirty-six clinically diagnosed and pathologically confirmed Alzheimer's disease (AD) patients included 13 with cortical and subcortical Lewy bodies (LBs). The patients with LBs appeared to constitute a distinct neuropathologic and clinical subset of AD, the Lewy body variant (LBV). The LBV group showed gross pallor of the substantia nigra, greater neuron loss in the locus ceruleus, substantia nigra, and substantia innominata, lower neocortical ChAT levels, and fewer midfrontal tangles than did the pure AD group, along with a high incidence of medial temporal lobe spongiform vacuolization. Analysis of neuropsychological tests from 9 LBV subjects and 9 AD patients matched for age and degree of dementia revealed greater deficits in attention, fluency, and visuospatial processing in the LBV group. Similar comparisons of neurologic examinations showed a significant increase in masked facies; in addition there was an increase in essential tremor, bradykinesia, mild neck rigidity, and slowing of rapid alternating movements in the LBV group. Extremity rigidity, flexed posture, resting tremor, or other classic parkinsonian features were not characteristic of the LBV patient. In some cases, it may be possible to diagnose LBV premortem on the basis of the clinical and neuropsychological features.

PMID 2153271  Neurology. 1990 Jan;40(1):1-8.
著者: I G McKeith, D Galasko, K Kosaka, E K Perry, D W Dickson, L A Hansen, D P Salmon, J Lowe, S S Mirra, E J Byrne, G Lennox, N P Quinn, J A Edwardson, P G Ince, C Bergeron, A Burns, B L Miller, S Lovestone, D Collerton, E N Jansen, C Ballard, R A de Vos, G K Wilcock, K A Jellinger, R H Perry
雑誌名: Neurology. 1996 Nov;47(5):1113-24.
Abstract/Text Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

PMID 8909416  Neurology. 1996 Nov;47(5):1113-24.
著者: I G McKeith, D W Dickson, J Lowe, M Emre, J T O'Brien, H Feldman, J Cummings, J E Duda, C Lippa, E K Perry, D Aarsland, H Arai, C G Ballard, B Boeve, D J Burn, D Costa, T Del Ser, B Dubois, D Galasko, S Gauthier, C G Goetz, E Gomez-Tortosa, G Halliday, L A Hansen, J Hardy, T Iwatsubo, R N Kalaria, D Kaufer, R A Kenny, A Korczyn, K Kosaka, V M Y Lee, A Lees, I Litvan, E Londos, O L Lopez, S Minoshima, Y Mizuno, J A Molina, E B Mukaetova-Ladinska, F Pasquier, R H Perry, J B Schulz, J Q Trojanowski, M Yamada, Consortium on DLB
雑誌名: Neurology. 2005 Dec 27;65(12):1863-72. doi: 10.1212/01.wnl.0000187889.17253.b1. Epub 2005 Oct 19.
Abstract/Text The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

PMID 16237129  Neurology. 2005 Dec 27;65(12):1863-72. doi: 10.1212/01.・・・
著者: Ian G McKeith, Bradley F Boeve, Dennis W Dickson, Glenda Halliday, John-Paul Taylor, Daniel Weintraub, Dag Aarsland, James Galvin, Johannes Attems, Clive G Ballard, Ashley Bayston, Thomas G Beach, Frédéric Blanc, Nicolaas Bohnen, Laura Bonanni, Jose Bras, Patrik Brundin, David Burn, Alice Chen-Plotkin, John E Duda, Omar El-Agnaf, Howard Feldman, Tanis J Ferman, Dominic Ffytche, Hiroshige Fujishiro, Douglas Galasko, Jennifer G Goldman, Stephen N Gomperts, Neill R Graff-Radford, Lawrence S Honig, Alex Iranzo, Kejal Kantarci, Daniel Kaufer, Walter Kukull, Virginia M Y Lee, James B Leverenz, Simon Lewis, Carol Lippa, Angela Lunde, Mario Masellis, Eliezer Masliah, Pamela McLean, Brit Mollenhauer, Thomas J Montine, Emilio Moreno, Etsuro Mori, Melissa Murray, John T O'Brien, Sotoshi Orimo, Ronald B Postuma, Shankar Ramaswamy, Owen A Ross, David P Salmon, Andrew Singleton, Angela Taylor, Alan Thomas, Pietro Tiraboschi, Jon B Toledo, John Q Trojanowski, Debby Tsuang, Zuzana Walker, Masahito Yamada, Kenji Kosaka
雑誌名: Neurology. 2017 Jul 4;89(1):88-100. doi: 10.1212/WNL.0000000000004058. Epub 2017 Jun 7.
Abstract/Text The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PMID 28592453  Neurology. 2017 Jul 4;89(1):88-100. doi: 10.1212/WNL.00・・・
著者: Horacio Kaufmann, Lucy Norcliffe-Kaufmann, Jose-Alberto Palma, Italo Biaggioni, Phillip A Low, Wolfgang Singer, David S Goldstein, Amanda C Peltier, Cyndia A Shibao, Christopher H Gibbons, Roy Freeman, David Robertson, Autonomic Disorders Consortium
雑誌名: Ann Neurol. 2017 Feb;81(2):287-297. doi: 10.1002/ana.24877.
Abstract/Text OBJECTIVE: To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.
METHODS: One hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests.
RESULTS: At enrollment, patients were 68 ± 12 years old (median ± interquartile range) and had had autonomic failure for 5 ± 7 years. Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell.
INTERPRETATION: Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287-297.

© 2017 American Neurological Association.
PMID 28093795  Ann Neurol. 2017 Feb;81(2):287-297. doi: 10.1002/ana.24・・・
著者: Wolfgang Singer, Sarah E Berini, Paola Sandroni, Robert D Fealey, Elizabeth A Coon, Mariana D Suarez, Eduardo E Benarroch, Phillip A Low
雑誌名: Neurology. 2017 Mar 21;88(12):1129-1136. doi: 10.1212/WNL.0000000000003737. Epub 2017 Feb 15.
Abstract/Text OBJECTIVE: Based on the observation that a subset of patients originally diagnosed with pure autonomic failure (PAF) eventually develops extrapyramidal or cerebellar involvement consistent with multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB), we aimed to identify predictors of progression of PAF to more sinister synucleinopathies.
METHODS: In this retrospective cohort study, we reviewed patients seen at Mayo Clinic Rochester by autonomic specialists between 2001 and 2011 and during initial evaluation diagnosed with orthostatic hypotension consistent with PAF (possible PAF). In order to assess for the presence or absence of progression, we identified patients with 3 years or more of in-person follow-up (stable PAF) or documented progression to another synucleinopathy (converters). To identify predictors of conversion, we assessed odds of conversion based on clinical, autonomic, and laboratory variables.
RESULTS: Among 318 patients fulfilling criteria for possible PAF, we identified 41 with stable PAF and 37 (12%) converters. Of those who evolved, 22 developed MSA, 11 developed PD/DLB, and 4 remained indeterminate. Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss, (3) severe bladder dysfunction, (4) supine norepinephrine >100 pg/mL, and (5) subtle motor signs at first presentation. Separate variables were found to predict conversion to PD/DLB. Composite conversion scores were generated based on individual predictors.
CONCLUSIONS: Over 10% of patients originally diagnosed with PAF eventually evolve to develop CNS involvement, most commonly MSA. A combination of variables allows for prediction of conversion.

© 2017 American Academy of Neurology.
PMID 28202694  Neurology. 2017 Mar 21;88(12):1129-1136. doi: 10.1212/W・・・
著者: Ian G McKeith, Tanis J Ferman, Alan J Thomas, Frédéric Blanc, Bradley F Boeve, Hiroshige Fujishiro, Kejal Kantarci, Cristina Muscio, John T O'Brien, Ronald B Postuma, Dag Aarsland, Clive Ballard, Laura Bonanni, Paul Donaghy, Murat Emre, James E Galvin, Douglas Galasko, Jennifer G Goldman, Stephen N Gomperts, Lawrence S Honig, Manabu Ikeda, James B Leverenz, Simon J G Lewis, Karen S Marder, Mario Masellis, David P Salmon, John Paul Taylor, Debby W Tsuang, Zuzana Walker, Pietro Tiraboschi, prodromal DLB Diagnostic Study Group
雑誌名: Neurology. 2020 Apr 28;94(17):743-755. doi: 10.1212/WNL.0000000000009323. Epub 2020 Apr 2.
Abstract/Text The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PMID 32241955  Neurology. 2020 Apr 28;94(17):743-755. doi: 10.1212/WNL・・・
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: T Miyamoto, M Miyamoto, Y Inoue, Y Usui, K Suzuki, K Hirata
雑誌名: Neurology. 2006 Dec 26;67(12):2236-8. doi: 10.1212/01.wnl.0000249313.25627.2e.
Abstract/Text Idiopathic REM sleep behavior disorder (RBD) may represent prodromal synucleinopathies. We report markedly reduced cardiac (123)I-metaiodobenzylguanidine uptake, consistent with the loss of sympathetic terminals, in idiopathic RBD. We also demonstrate that this reduction is of the same magnitude as that found in patients with Parkinson disease. The results are consistent with the hypothesis that idiopathic RBD in older patients is a forme fruste of Lewy body disease.

PMID 17190953  Neurology. 2006 Dec 26;67(12):2236-8. doi: 10.1212/01.w・・・
著者: M Yoshita, J Taki, K Yokoyama, M Noguchi-Shinohara, Y Matsumoto, K Nakajima, M Yamada
雑誌名: Neurology. 2006 Jun 27;66(12):1850-4. doi: 10.1212/01.wnl.0000219640.59984.a7.
Abstract/Text OBJECTIVE: To evaluate the diagnostic reliability of cardiac iodine-123 metaiodobenzylguanidine ((123)I-MIBG) radioactivity in discriminating dementia with Lewy bodies (DLB) from Alzheimer disease (AD) regardless of parkinsonism.
BACKGROUND: The diagnosis of DLB may be confounded by the absence of parkinsonism. This highlights the need to improve the accuracy of antemortem diagnosis of DLB without parkinsonism.
METHODS: Cardiac sympathetic denervation was examined using myocardial (123)I-MIBG scintigraphy in 37 patients with DLB, 42 patients with AD, and 10 normal elderly controls. The DLB patients consisted of seven patients without parkinsonism (DLB/P-) and 30 patients with parkinsonism (DLB/P+) at the time of the study.
RESULTS: The heart-to-mediastinum uptake ratio (H/M ratio) of myocardial MIBG uptake was decreased in both the DLB groups vs the AD group (p < 0.0001) and control group (p < 0.0001). The washout rate (WR) was higher in the DLB group than in the control group (p < 0.0001) and AD group (p < 0.0001). No differences were found between the AD and control groups or between the DLB/P+ and DLB/P- groups in either the early or delayed H/M ratio or WR. In discriminating between DLB and AD, regardless of parkinsonism, the delayed H/M ratio had a sensitivity of 100%, a specificity of 100%, and a positive predictive value of 100% at a cutoff value of 1.68.
CONCLUSIONS: Our results indicate that dementia with Lewy bodies results in cardiac sympathetic denervation and that iodine-123 metaiodobenzylguanidine myocardial scintigraphy is a sensitive tool for discriminating dementia with Lewy bodies from Alzheimer disease even in patients without parkinsonism.

PMID 16801649  Neurology. 2006 Jun 27;66(12):1850-4. doi: 10.1212/01.w・・・
著者: Panitha Jindahra, Athasit Vejjajiva, Rawiphan Witoonpanich, Rojana Sirisriro, Chanika Sritara, Teeratorn Pulkes
雑誌名: J Med Assoc Thai. 2004 Oct;87(10):1176-81.
Abstract/Text OBJECTIVE: Differentiation of dementia with Lewy bodies (DLB), vascular dementia (VAD), and Alzheimer's disease (AD) is difficult in clinical practice. Several new techniques have been used for differentiation of various types of dementia. Among these techniques 123I-meta-iodobenzylguanidine (MIBG) uptake was reported to have benefit in distinguishing DLB from AD. The authors study the role of MIBG as a tool for differentiation of DLB, AD and VAD.
METHOD: Patients with dementia were recruited to the study by DSMIIIR criteria. Diagnosis of each dementia type was made by standard clinical criteria. Brain imagings and 131I-MIBG uptake were performed in all the studied patients.
RESULTS: Five DLB, 3 AD and 3 VAD patients were clinically diagnosed. The heart/mediastinum (H/M) ratio in 4 out of 5 in DLB was significantly lower than H/M ratio in patients with AD and VAD. AD patients had the highest uptake of MIBG MIBG uptake of VAD patients was in the range between AD and DLB but the values were close to the AD group.
CONCLUSIONS: 131I-MIBG is helpful in differentiating DLB from AD.

PMID 15560694  J Med Assoc Thai. 2004 Oct;87(10):1176-81.
著者: Giorgio Treglia, Ernesto Cason, Antonella Stefanelli, Fabrizio Cocciolillo, Daniela Di Giuda, Giorgio Fagioli, Alessandro Giordano
雑誌名: Clin Auton Res. 2012 Feb;22(1):43-55. doi: 10.1007/s10286-011-0135-5. Epub 2011 Jul 27.
Abstract/Text OBJECTIVE: Differential diagnosis between Parkinson's disease (PD) and other Parkinsonism using clinical criteria or imaging methods is often difficult. The purpose of this study is to systematically review and meta-analyze published data about the diagnostic performance of myocardial innervation imaging using (123)I-metaiodobenzylguanidine (MIBG) scintigraphy in differential diagnosis between PD and other Parkinsonism.
METHODS: A comprehensive computer literature search of studies published through March 2011 regarding MIBG scintigraphy in patients with PD and other Parkinsonism was performed in PubMed/MEDLINE and Embase databases. Only studies in which MIBG scintigraphy was performed for differential diagnosis between PD and other Parkinsonism were selected. Pooled sensitivity, pooled specificity and area under the ROC curve were calculated to measure the accuracy of MIBG scintigraphy in differential diagnosis between PD and other Parkinsonism.
RESULTS: Nineteen studies comprising 1,972 patients (1,076 patients with PD, 117 patients with other Lewy body diseases and 779 patients with other diseases) were included in this meta-analysis. The pooled sensitivity of MIBG scintigraphy in detecting PD was 88% (95% CI 86-90%); the pooled specificity of MIBG scintigraphy in discriminating between PD and other Parkinsonism was 85% (95% CI 81-88%). The area under the ROC curve was 0.93.
CONCLUSIONS: In patients with clinically suspected PD, myocardial innervation imaging demonstrated high sensitivity and specificity. MIBG scintigraphy is an accurate test in this setting. Nevertheless, possible causes of false-negative and false-positive results should be kept in mind when interpreting the scintigraphic results.

PMID 21792729  Clin Auton Res. 2012 Feb;22(1):43-55. doi: 10.1007/s102・・・
著者: Alisha E King, Jim Mintz, Donald R Royall
雑誌名: Mov Disord. 2011 Jun;26(7):1218-24. doi: 10.1002/mds.23659. Epub 2011 Apr 7.
Abstract/Text Patients with parkinsonism pose a diagnostic challenge. Parkinson's disease may be difficult to distinguish from multiple system atrophy and progressive supranuclear palsy, whereas Parkinson's disease and dementia with Lewy bodies can be difficult to distinguish from Alzheimer's disease and other dementias. A number of studies have found diminished cardiac (123) I-metaiodobenzylguanidine uptake in Lewy body-related conditions (Parkinson's disease and Lewy body dementia). In 2005, the Dementia With Lewy Bodies Consortium considered (123) I-metaiodobenzylguanidine cardiac scintigraphy a "supportive" diagnostic feature, based on limited evidence. We report a meta-analysis of the literature and an assessment of the utility of (123) I-metaiodobenzylguanidine for the diagnosis of dementia with Lewy bodies and Parkinson's disease. A search was conducted of articles published between 1950 and June 2010. Forty-six studies involving neuropsychiatric and movement disorders, comprising 2680 subjects, were included in the analysis. A mixed-effects regression model was used to analyze the delayed mean heart-to-mediastinum ratio of (123) I-metaiodobenzylguanidine uptake. (123) I-metaiodobenzylguanidine cardiac scintigraphy sensitively detected and specifically distinguished 2 diagnostic clusters: (1) Parkinson's disease, dementia with Lewy bodies, and rapid eye movement sleep behavior disorder; and (2) normal controls and patients with Alzheimer's disease, multiple system atrophy, progressive supranuclear palsy, vascular dementia, and frontotemporal dementia. The area under the receiver operating characteristic curve was 0.987 at a cluster discriminatory heart-to-mediastinum ratio threshold of 1.77. This threshold yielded 94% sensitivity and 91% specificity for the discrimination of these diagnostic clusters. (123) I-metaiodobenzylguanidine cardiac scintigraphy can accurately distinguish between 2 movement disorders, Parkinson's disease and multiple system atrophy, and between 2 common causes of dementia, Alzheimer's disease and dementia with Lewy bodies. © 2011 Movement Disorder Society.

Copyright © 2011 Movement Disorder Society.
PMID 21480373  Mov Disord. 2011 Jun;26(7):1218-24. doi: 10.1002/mds.23・・・
著者: Giorgio Treglia, Ernesto Cason
雑誌名: J Neuroimaging. 2012 Apr;22(2):111-7. doi: 10.1111/j.1552-6569.2010.00532.x. Epub 2010 Nov 17.
Abstract/Text BACKGROUND AND PURPOSE: This study was designed to review the diagnostic performance of myocardial innervation imaging using iodine-123-metaiodobenzylguanidine (MIBG) scintigraphy in differential diagnosis between dementia with Lewy bodies (DLB) and other dementias.
METHODS: A comprehensive computer literature search of studies published through May 2010 regarding MIBG scintigraphy in patients with DLB was performed in PubMed/MEDLINE and Embase databases. Only studies in which MIBG scintigraphy was performed for differential diagnosis between DLB and other dementias were selected. Pooled sensitivity and specificity of MIBG scintigraphy were presented with a 95% confidence interval (CI). The area under the ROC curve was calculated to measure the accuracy of MIBG scintigraphy in differential diagnosis between Lewy body diseases and other dementias.
RESULTS: Ultimately, we identified 8 studies comprising a total of 346 patients with dementia (152 patients with DLB and 194 patients with other dementias). The pooled sensitivity of MIBG scintigraphy in detection of DLB was 98% (95% CI, 94-100%); the pooled specificity of MIBG scintigraphy in differential diagnosis between DLB and other dementias was 94% (95% CI, 90-97%). The area under the ROC curve was .99.
CONCLUSIONS: Myocardial innervation imaging with MIBG scintigraphy demonstrated high pooled sensitivity and specificity in patients with suspected DLB. MIBG scintigraphy is an accurate test for differential diagnosis between DLB and other dementias.

Copyright © 2010 by the American Society of Neuroimaging.
PMID 21091814  J Neuroimaging. 2012 Apr;22(2):111-7. doi: 10.1111/j.15・・・
著者: Yoshikuni Mizuno
雑誌名: Nihon Rinsho. 2004 Sep;62(9):1597-600.
Abstract/Text There has been lots of progress in Parkinson's disease. First of all, in Japan, a guideline for the treatment of Parkinson's disease was published. This guideline contains both EBM based systematic review of every drugs being used in the treatment of Parkinson's disease including those drugs for the management of side effects and other problems arising during the course of the treatment and an algorithm of the practical treatment of Parkinson's disease patients. This is an official publication of Japanese Neurological Society. In the diagnosis of Parkinson's disease, many specialists in Parkinson's disease have recognized the usefulness of MIBG SPECT of the cardiac sympathetic endings. MIBG uptake shows remarkable decrease in Lewy body positive Parkinson's disease patients from the early stage except for some of the stage I patients. In the basic aspect, studies on familial forms of Parkinson's disease have contributed a lot to the understanding of the pathogenesis of sporadic Parkinson's disease. Mutations of alpha-synuclein cause autosomal dominant Parkinson's disease. Recently, triplication of one of the alpha-synuclein genes was found as the third mutation of PARK1. Thus just overproduction of normal alpha-synuclein is toxic to nigral neurons. In this form and sporadic Parkinson's disease, oxidative damage plays an important role in nigral neurodegeneration. PARK2 is caused by mutations of the parkin gene. Parkin protein is an ubiquitin-protein ligase. In this form also, oxidative damage appears to be operating in neurodegeneration. Thus a common mechanism appears to be present in different forms of Parkinson's disease. Future investigation to find neuroprotective drugs should take this concept of common mechanism into their research strategies.

PMID 15462371  Nihon Rinsho. 2004 Sep;62(9):1597-600.
著者: Rosie Watson, Andrew M Blamire, John T O'Brien
雑誌名: Dement Geriatr Cogn Disord. 2009;28(6):493-506. doi: 10.1159/000264614. Epub 2009 Dec 8.
Abstract/Text Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share common clinical, neuropsychological and pathological features. In clinical diagnosis, distinguishing between these conditions and other dementia subtypes such as Alzheimer's disease (AD) can be difficult. Despite the development of consensus diagnostic criteria, sensitivity for diagnosis remains low, especially outside specialist centres. Neuroimaging techniques using magnetic resonance (MR) can assess changes in structure, microstructure through diffusion tensor imaging and metabolism using spectroscopy and cerebral perfusion. Identification of such changes may contribute to our understanding of the disease process, assist in refining ante-mortem diagnosis and allow disease progression to be measured. This may be both clinically useful and a tool for assessing outcome in therapeutic trials. DLB and PDD share a similar pattern of MRI changes including global brain volume loss, a predominantly subcortical pattern of cerebral atrophy and structural preservation of the medial temporal lobe compared to AD. This review summarises the application and findings from MR studies in DLB and PDD to provide further insight into the similarities between the conditions, highlight the potential for the clinical application of MR techniques and outline promising areas for further research.

PMID 19996594  Dement Geriatr Cogn Disord. 2009;28(6):493-506. doi: 10・・・
著者: Seok Ming Lim, Andrew Katsifis, Victor L Villemagne, Rene Best, Gareth Jones, Michael Saling, Jennifer Bradshaw, John Merory, Michael Woodward, Malcolm Hopwood, Christopher C Rowe
雑誌名: J Nucl Med. 2009 Oct;50(10):1638-45. doi: 10.2967/jnumed.109.065870. Epub 2009 Sep 16.
Abstract/Text UNLABELLED: Neuroimaging is increasingly used to supplement the clinical diagnosis of dementia with Lewy bodies (DLB) by showing reduced occipital metabolism and perfusion and reduced striatal dopaminergic innervation. We aimed to optimize the interpretation of (18)F-FDG PET images for differentiating DLB from Alzheimer disease (AD) and to compare the results with dopamine transporter imaging using (123)I-beta-carbomethoxy-3ss-(4-iodophenyl)tropane ((123)I-beta-CIT) SPECT.
METHODS: Fourteen subjects with a clinical diagnosis of DLB and 10 with AD underwent both (18)F-FDG PET and (123)I-beta-CIT SPECT. Four DLB and 1 AD diagnoses were subsequently confirmed at autopsy. Diagnostic accuracy was calculated for visual interpretation by 3 readers of standard 3-plane and stereotactic surface projection (18)F-FDG PET images, receiver-operating-characteristic analysis of regional (18)F-FDG uptake, and a cutoff value for the striatal-to-occipital binding ratio of beta-CIT defined by receiver-operating-characteristic analysis.
RESULTS: Visual interpretation of 3-plane (18)F-FDG PET images had a sensitivity of 83% and specificity of 93% for DLB, slightly higher than the results with the stereotactic surface projection images. Regionally, hypometabolism in the lateral occipital cortex had the highest sensitivity (88%), but relative preservation of the mid or posterior cingulate gyrus (cingulate island sign) had the highest specificity (100%). Region-of-interest analysis revealed that occipital hypometabolism and relative preservation of the posterior cingulate both had a sensitivity of 77% and specificity of 80%. beta-CIT achieved 100% accuracy and greater effect size than did (18)F-FDG PET (Cohen d = 4.1 vs. 1.9).
CONCLUSION: Both (18)F-FDG PET and (123)I-beta-CIT SPECT appear useful for the diagnosis of DLB, although the latter provides more robust results. The cingulate island sign may enhance the specificity of (18)F-FDG PET.

PMID 19759102  J Nucl Med. 2009 Oct;50(10):1638-45. doi: 10.2967/jnume・・・
著者: Ian McKeith, John O'Brien, Zuzana Walker, Klaus Tatsch, Jan Booij, Jacques Darcourt, Alessandro Padovani, Raffaele Giubbini, Ubaldo Bonuccelli, Duccio Volterrani, Clive Holmes, Paul Kemp, Naji Tabet, Ines Meyer, Cornelia Reininger, DLB Study Group
雑誌名: Lancet Neurol. 2007 Apr;6(4):305-13. doi: 10.1016/S1474-4422(07)70057-1.
Abstract/Text BACKGROUND: Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand (123)I-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included.
METHODS: We did a phase III study in which we used a (123)I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0.80) and specificity (0.85) targets and prespecified lower thresholds (sensitivity 0.65, specificity 0.73) using one-sided binomial tests with a significance level of alpha=0.025.
FINDINGS: Abnormal scans had a mean sensitivity of 77.7% for detecting clinical probable DLB, with specificity of 90.4% for excluding non-DLB dementia, which was predominantly due to Alzheimer's disease. A mean value of 85.7% was achieved for overall diagnostic accuracy, 82.4% for positive predictive value, and 87.5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's kappa=0.87). The procedure was well tolerated with few adverse events.
INTERPRETATION: A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.

PMID 17362834  Lancet Neurol. 2007 Apr;6(4):305-13. doi: 10.1016/S1474・・・
著者: Marine Soret, Pierre Malick Koulibaly, Jacques Darcourt, Irène Buvat
雑誌名: Eur J Nucl Med Mol Imaging. 2006 Sep;33(9):1062-72. doi: 10.1007/s00259-005-0003-4. Epub 2006 Apr 26.
Abstract/Text PURPOSE: In single-photon emission computed tomography (SPECT) of the dopaminergic system, measurements of striatal uptake are useful for diagnosis and patient follow-up but are strongly biased by the partial volume effect (PVE). We studied whether PVE correction might improve patient classification based on binding potential (BP) measurements.
METHODS: Patients with a probable diagnosis of dementia with Lewy bodies (DLB, 10 patients) or Alzheimer's disease (AD, 13 patients) were studied by( 123)I-FP-CIT SPECT. SPECT images were reconstructed with and without PVE correction. Each patient SPECT scan was also simulated to obtain SPECT data whose characteristics were fully known. In addition, 17 SPECT scans were simulated with striatal uptake values mimicking pre-symptomatic cases of DLB.
RESULTS: Without PVE correction, mean putamen BP values were 2.9+/-0.4 and 0.9+/-0.2 for AD and DLB patients respectively, while with PVE correction, they were 8.6+/-1.5 and 1.9+/-0.5 respectively. All patients were properly identified as having AD or DLB when considering mean putamen BP measured on their real or simulated SPECT scan, with and without PVE correction. All 30 simulations mimicking pre-symptomatic DLB and AD patients were accurately classified with PVE correction, but without PVE correction 15 mean putamen BP values were in a range where AD and DLB could not be distinguished.
CONCLUSION: We conclude that putamen BP values measured without PVE correction can be used to differentiate probable DLB and AD due to the already severe reduction in dopamine transporter levels. PVE correction appeared useful for accurate differential diagnosis between AD and pre-symptomatic DLB.

PMID 16639610  Eur J Nucl Med Mol Imaging. 2006 Sep;33(9):1062-72. doi・・・
著者: J Eerola, P J Tienari, S Kaakkola, P Nikkinen, J Launes
雑誌名: J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1211-6. doi: 10.1136/jnnp.2004.045237.
Abstract/Text OBJECTIVE: To assess the accuracy and clinical usefulness of [(123)I]beta-CIT (2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) SPECT in the differential diagnosis of Parkinson's disease.
SUBJECTS: 185 consecutive patients with symptoms of movement disorder were studied. The diagnoses were Parkinson's disease (92), essential tremor (16), vascular parkinsonism (15), various Parkinson plus syndromes (P+) (12), dementia with Lewy bodies (DLB) (5), dystonia (5), drug induced movement disorder (12), and other diagnoses (8). A reference group (psychogenic parkinsonism) comprised 20 subjects with complaints suggesting extrapyramidal disease but with no unequivocal signs on clinical examination and no abnormalities on brain imaging.
RESULTS: beta-CIT uptake was significantly lower in the whole striatum as well as separately in the putamen and in the caudate nucleus in Parkinson's disease than in the reference group or in drug induced movement disorder, essential tremor, or dystonia. The uptake of beta-CIT in the vascular parkinsonism group was heterogeneous and mean beta-CIT uptake fell between the reference group and the Parkinson's disease group. In the P+ and DLB groups the striatal uptake ratios overlapped those of the Parkinson's disease group.
CONCLUSIONS: [(123)I]beta-CIT SPECT may not be as useful a tool in the clinical differential diagnosis of Parkinson's disease as was previously believed, but it was 100% sensitive and specific for the diagnosis in younger patients (age <55 years). In older patients (age >55 years) specificity was substantially lower (68.5%). This differential specificity reflected the different distribution of differential diagnostic disorders (P+, DLB, vascular parkinsonism) in the older and younger age groups.

PMID 16107353  J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1211-6. d・・・
著者: Sean J Colloby, E David Williams, David J Burn, Jim J Lloyd, Ian G McKeith, John T O'Brien
雑誌名: Eur J Nucl Med Mol Imaging. 2005 Oct;32(10):1176-85. doi: 10.1007/s00259-005-1830-z. Epub 2005 Jun 2.
Abstract/Text PURPOSE: The objective of this study was to investigate the rate of progression of nigrostriatal dopaminergic loss in subjects with dementia with Lewy bodies (DLB), Parkinson's disease (PD) and PD with dementia (PDD) using serial 123I-FP-CIT SPECT imaging. We hypothesised that striatal rates of decline in patients would be greater than in controls, and that DLB and PDD would show similar rates, reflecting the similarity in neurobiological mechanisms of dopaminergic loss between the two disorders.
METHODS: We studied 20 patients with DLB, 20 with PD, 15 with PDD and 22 healthy age-matched controls. Semi-automated region of interest (ROI) analysis was performed on both baseline and repeat scans for each subject and mean striatal uptake ratios (caudate, anterior and posterior putamen) were calculated.
RESULTS: Rates of decline in striatal binding between groups were assessed using ANCOVA. Significant differences between patients and controls were observed in caudate (DLB, PD, PDD, p< or =0.01), anterior putamen (DLB, PDD, p< or =0.05; PD, p=0.07) and posterior putamen (DLB, PD, PDD, p<0.006). Rates of decline were similar between DLB, PD and PDD.
CONCLUSION: In conclusion, this is the first study to show that significant progressive dopaminergic loss occurs in DLB and PDD using serial 123I-FP-CIT SPECT. Dementia severity and motor impairment were correlated with decline, suggesting that dopaminergic loss may play an important role in cognitive as well as motor features.

PMID 15931516  Eur J Nucl Med Mol Imaging. 2005 Oct;32(10):1176-85. do・・・
著者: Sean J Colloby, John T O'Brien, John D Fenwick, Michael J Firbank, David J Burn, Ian G McKeith, E David Williams
雑誌名: Neuroimage. 2004 Nov;23(3):956-66. doi: 10.1016/j.neuroimage.2004.06.045.
Abstract/Text Dopaminergic loss can be visualised using (123)I-FP-CIT single photon emission computed tomography (SPECT) in several disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Most previous SPECT studies have adopted region of interest (ROI) methods for analysis, which are subjective and operator-dependent. The purpose of this study was to investigate differences in striatal binding of (123)I-FP-CIT SPECT using the automated technique of statistical parametric mapping (SPM99) in subjects with DLB, Alzheimer's disease (AD), PD and healthy age-matched controls. This involved spatial normalisation of each subject's image to a customised template, followed by smoothing and intensity normalisation of each image to its corresponding mean occipital count per voxel. Group differences were assessed using a two-sample t test. Applying a height threshold of P
PMID 15528096  Neuroimage. 2004 Nov;23(3):956-66. doi: 10.1016/j.neuro・・・
著者: Sean J Colloby, Shane McParland, John T O'Brien, Johannes Attems
雑誌名: Brain. 2012 Sep;135(Pt 9):2798-808. doi: 10.1093/brain/aws211.
Abstract/Text Investigation of dopaminergic transporter loss in vivo using (123)I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane single photon emission computed tomography has been widely used as a diagnostic aid in Lewy body disease. However, it is not clear whether the pathological basis for the imaging changes observed reflects loss of dopaminergic transporter expressing neurons because of cell death or dysfunctional neurons due to possible nigral and/or striatal neurodegenerative pathology. We aimed to investigate the influence of nigral neuronal loss as well as nigral (α-synuclein, tau) and striatal (α-synuclein, tau, amyloid β) pathology on striatal uptake in a cohort of autopsy-confirmed Alzheimer's disease (n = 4), dementia with Lewy bodies (n = 7) and Parkinson's disease dementia (n = 12) cases. Subjects underwent ante-mortem dopaminergic scanning and post-mortem assessments (mean interval 3.7 years). Striatal binding (caudate, anterior and posterior putamen) was estimated using region of interest procedures while quantitative neuropathological measurements of α-synuclein, tau and amyloid β were carried out. Similarly, nigral neuronal density was assessed quantitatively. Stepwise linear regression was performed to identify significant pathological predictors of striatal binding. In all striatal regions, image uptake was associated with nigral dopaminergic neuronal density (P ≤ 0.04) but not α-synuclein (P ≥ 0.46), tau (P ≥ 0.18) or amyloid β (P ≥ 0.22) burden. The results suggest that reduced uptake in vivo may be influenced considerably by neuronal loss rather than the presence of pathological lesions, in particular those related to Alzheimer's disease and Lewy body dementias. However, dysfunctional nigral neurons may have an additional effect on striatal uptake in vivo but their respective role remains to be elucidated.

PMID 22961551  Brain. 2012 Sep;135(Pt 9):2798-808. doi: 10.1093/brain/・・・
著者: Paul M Kemp, Sandra A Hoffmann, Livia Tossici-Bolt, John S Fleming, Clive Holmes
雑誌名: Nucl Med Commun. 2007 Jun;28(6):451-6. doi: 10.1097/MNM.0b013e328155d143.
Abstract/Text OBJECTIVE: To assess the utility of the appearances of occipital lobe perfusion on HMPAO SPECT in the diagnosis of dementia with Lewy bodies (DLB) using the 123I-FP-CIT findings as the diagnostic 'gold standard'.
METHODS: Eighty-four consecutive patients underwent both HMPAO SPECT and 123I-FP-CIT as part of their routine investigations for suspected DLB.
RESULTS: Thirty-nine of the 84 FP-CIT scans were abnormal indicating a prevalence of 44% of patients with DLB in this series. In those patients classified as DLB, 28% of HMPAO SPECT scans demonstrated occipital hypoperfusion. In those patients with a dementia other than DLB 31% of patients demonstrated occipital hypoperfusion (P=0.8).
CONCLUSION: Occipital lobe hypoperfusion as demonstrated by HMPAO SPECT in patients with suspected Lewy body dementia does not appear to be able to either rule in, or rule out, the diagnosis of DLB.

PMID 17460535  Nucl Med Commun. 2007 Jun;28(6):451-6. doi: 10.1097/MNM・・・
著者: M J Firbank, S J Colloby, D J Burn, I G McKeith, J T O'Brien
雑誌名: Neuroimage. 2003 Oct;20(2):1309-19. doi: 10.1016/S1053-8119(03)00364-1.
Abstract/Text Tc99 HMPAO SPECT and T1 weighted 3D MRI scans were acquired in cognitively intact subjects with Parkinson's disease (PD) (n = 31), and in PD subjects with dementia (PDD) (n = 34), healthy controls (n = 37), those with Alzheimer's disease (AD) (n = 32), and those with dementia with Lewy bodies (DLB) (n = 15). We used SPM99 to look for regions which showed a reduction in perfusion on SPECT not related to associated structural brain changes assessed by a MRI scan. The precuneus and inferior lateral parietal regions showed a perfusion deficit in Parkinson's disease with dementia, similar to the pattern observed in DLB. In comparison, AD showed a perfusion deficit in the midline parietal region, in a more anterior and inferior location than in PDD, involving the posterior cingulate as well as the precuneus. The perfusion deficits in PDD are similar those in DLB, and in a location associated with visual processing, and may be associated with the visuospatial perception deficits which are present in persons with DLB and PDD.

PMID 14568499  Neuroimage. 2003 Oct;20(2):1309-19. doi: 10.1016/S1053-・・・
著者: Sean J Colloby, John D Fenwick, E David Williams, Sean M Paling, Kyriakos Lobotesis, Clive Ballard, Ian McKeith, John T O'Brien
雑誌名: Eur J Nucl Med Mol Imaging. 2002 May;29(5):615-22. doi: 10.1007/s00259-002-0778-5. Epub 2002 Mar 5.
Abstract/Text Differences in regional cerebral blood flow (rCBF) between subjects with Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and healthy volunteers were investigated using statistical parametric mapping (SPM99). Forty-eight AD, 23 DLB and 20 age-matched control subjects participated. Technetium-99m hexamethylpropylene amine oxime (HMPAO) brain single-photon emission tomography (SPET) scans were acquired for each subject using a single-headed rotating gamma camera (IGE CamStar XR/T). The SPET images were spatially normalised and group comparison was performed by SPM99. In addition, covariate analysis was undertaken on the standardised images taking the Mini Mental State Examination (MMSE) scores as a variable. Applying a height threshold of P < or = 0.001 uncorrected, significant perfusion deficits in the parietal and frontal regions of the brain were observed in both AD and DLB groups compared with the control subjects. In addition, significant temporoparietal perfusion deficits were identified in the AD subjects, whereas the DLB patients had deficits in the occipital region. Comparison of dementia groups (height threshold of P < or = 0.01 uncorrected) yielded hypoperfusion in both the parietal [Brodmann area (BA) 7] and occipital (BA 17, 18) regions of the brain in DLB compared with AD. Abnormalities in these areas, which included visual cortex and several areas involved in higher visual processing and visuospatial function, may be important in understanding the visual hallucinations and visuospatial deficits which are characteristic of DLB. Covariate analysis indicated group differences between AD and DLB in terms of a positive correlation between cognitive test score and temporoparietal blood flow. In conclusion, we found evidence of frontal and parietal hypoperfusion in both AD and DLB, while temporal perfusion deficits were observed exclusively in AD and parieto-occipital deficits in DLB.

PMID 11976799  Eur J Nucl Med Mol Imaging. 2002 May;29(5):615-22. doi:・・・
著者: E K Doubleday, J S Snowden, A R Varma, D Neary
雑誌名: J Neurol Neurosurg Psychiatry. 2002 May;72(5):602-7.
Abstract/Text OBJECTIVES: To determine whether dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) can be differentiated on the basis of qualitative performance characteristics during neuropsychological evaluation.
METHODS: Forty one patients with clinically defined DLB were matched with 26 patients with AD for age, illness duration, nature and severity of cognitive deficits, and regional blood flow distribution on SPECT. The presence or absence of a set of qualitative performance characteristics, observed and recorded during the patients' initial cognitive evaluation, was identified by retrospective analysis of patients' records and the groups compared.
RESULTS: Inattention, visual distractibility, impairments in establishing and shifting mental set, incoherence, confabulatory responses, perseveration, and intrusions were significantly more common in DLB than AD. Intrusions were particularly common in DLB, occurring in 78% of the group. They included externally cued intrusions arising from the visual environment, a feature never seen in AD. In a stepwise logistic regression analysis impaired mental set shifting, perseveration, and the presence of intrusions correctly classified 79% of patients.
CONCLUSION: It is possible to differentiate DLB and AD on the basis of qualitative features of performance. As many features are amenable to detection at clinical interview, they ought to contribute to clinicians' diagnostic armoury, leading to improved clinical recognition of DLB.

PMID 11971046  J Neurol Neurosurg Psychiatry. 2002 May;72(5):602-7.
著者: Kazunari Ishii, Tomonori Kanda, Takafumi Uemura, Naokazu Miyamoto, Toshiki Yoshikawa, Kenichi Shimada, Shingo Ohkawa, Satoshi Minoshima
雑誌名: Eur J Nucl Med Mol Imaging. 2009 May;36(5):831-40. doi: 10.1007/s00259-008-1051-3. Epub 2009 Jan 16.
Abstract/Text PURPOSE: To develop a computer-assisted automated diagnostic system to distinguish among Alzheimer disease (AD), dementia with Lewy bodies (DLB), and other degenerative disorders in patients with mild dementia.
METHODS: Single photon emission computed tomography (SPECT) images with injection of N-Isopropyl-p-[(123)I]iodoamphetamine (IMP) were obtained from patients with mild degenerative dementia. First, datasets from 20 patients mild AD, 15 patients with dementia with DLB, and 17 healthy controls were used to develop an automated diagnosing system based on three-dimensional stereotactic surface projections (3D-SSP). AD- and DLB-specific regional templates were created using 3D-SSP, and critical Z scores in the templates were established. Datasets from 50 AD patients, 8 DLB patients, and 10 patients with non-AD/DLB type degenerative dementia (5 with frontotemporal dementia and 5 with progressive supranuclear palsy) were then used to test the diagnostic accuracy of the optimized automated system in comparison to the diagnostic interpretation of conventional IMP-SPECT images. These comparisons were performed to differentiate AD and DLB from non-AD/DLB and to distinguish AD from DLB. A receiver operating characteristic (ROC) analysis was performed.
RESULTS: The area under the ROC curve (Az) and the accuracy of the automated diagnosis system were 0.89 and 82%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the visual inspection were 0.84 and 77%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the combination of visual inspection and this system were 0.96 and 91%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 66%, respectively, for AD vs. DLB patients.
CONCLUSION: The system developed in the present study achieved as good discrimination of AD, DLB, and other degenerative disorders in patients with mild dementia as the commonly performed visual inspection of conventional SPECT images. A combination of visual inspection and this system is helpful in the differential diagnosis of patients with mild dementia.

PMID 19148640  Eur J Nucl Med Mol Imaging. 2009 May;36(5):831-40. doi:・・・
著者: Shuhei Kasama, Hisao Tachibana, Keita Kawabata, Hiroo Yoshikawa
雑誌名: Dement Geriatr Cogn Disord. 2005;19(5-6):266-75. doi: 10.1159/000084551. Epub 2005 Mar 18.
Abstract/Text Regional brain perfusion was analyzed using single-photon emission computed tomography with three-dimensional stereotactic surface projections (3D-SSP) in 69 patients with Parkinson's disease (PD), 16 patients with dementia with Lewy bodies (DLB) and 15 patients with Alzheimer's disease (AD), and compared with that in 24 age-equivalent normal subjects. Nondemented PD patients revealed less parietal and frontal flow than controls. With mental impairment, flow reduction extended to other areas including occipital regions. PD with dementia and DLB showed similar reduction patterns, although frontal flow showed a greater reduction in DLB. AD showed little occipital reduction, but a severe parieto-temporal reduction. Thus, 3D-SSP appears to be useful in the detection of cortical lesions and the differential diagnosis of patients with cognitive impairment.

PMID 15775716  Dement Geriatr Cogn Disord. 2005;19(5-6):266-75. doi: 1・・・
著者: T Imamura, K Ishii, M Sasaki, H Kitagaki, S Yamaji, N Hirono, T Shimomura, M Hashimoto, S Tanimukai, H Kazui, E Mori
雑誌名: Neurosci Lett. 1997 Oct 10;235(1-2):49-52.
Abstract/Text Regional cerebral metabolic rate of glucose (rCMRglc) was studied in 19 patients with a clinical diagnosis of dementia with Lewy bodies (DLB) and 19 patients with a clinical diagnosis of Alzheimer's disease (AD), using [18F]fluorodeoxyglucose ([18F]FDG) and positron emission tomography (PET). The two groups were matched with age, gender, disease duration and severity of cognitive disturbances. In 'dementia with Lewy bodies' (DLB) patients, when compared with AD patients, significant rCMRglc decreases were distributed in the temporo-parieto-occipital association cortices and the cerebellar hemispheres. In contrast, the medial temporal and cingulate rCMRglc were significantly lower in AD patients than those in DLB patients. These different regional emphases of glucose hypometabolism are consistent with the pathological and neurochemical differences between DLB and AD and explain the different clinical features of the two diseases.

PMID 9389593  Neurosci Lett. 1997 Oct 10;235(1-2):49-52.
著者: Jonathan Graff-Radford, Melissa E Murray, Val J Lowe, Bradley F Boeve, Tanis J Ferman, Scott A Przybelski, Timothy G Lesnick, Matthew L Senjem, Jeffrey L Gunter, Glenn E Smith, David S Knopman, Clifford R Jack, Dennis W Dickson, Ronald C Petersen, Kejal Kantarci
雑誌名: Neurology. 2014 Aug 26;83(9):801-9. doi: 10.1212/WNL.0000000000000734. Epub 2014 Jul 23.
Abstract/Text OBJECTIVES: To investigate clinical, imaging, and pathologic associations of the cingulate island sign (CIS) in dementia with Lewy bodies (DLB).
METHODS: We retrospectively identified and compared patients with a clinical diagnosis of DLB (n=39); patients with Alzheimer disease (AD) matched by age, sex, and education (n=39); and cognitively normal controls (n=78) who underwent 18F-fluorodeoxyglucose (FDG) and C11 Pittsburgh compound B (PiB)-PET scans. Among these patients, we studied those who came to autopsy and underwent Braak neurofibrillary tangle (NFT) staging (n=10).
RESULTS: Patients with a clinical diagnosis of DLB had a higher ratio of posterior cingulate to precuneus plus cuneus metabolism, cingulate island sign (CIS), on FDG-PET than patients with AD (p<0.001), a finding independent of β-amyloid load on PiB-PET (p=0.56). Patients with CIS positivity on visual assessment of FDG-PET fit into the group of high- or intermediate-probability DLB pathology and received clinical diagnosis of DLB, not AD. Higher CIS ratio correlated with lower Braak NFT stage (r=-0.96; p<0.001).
CONCLUSIONS: Our study found that CIS on FDG-PET is not associated with fibrillar β-amyloid deposition but indicates lower Braak NFT stage in patients with DLB. Identifying biomarkers that measure relative contributions of underlying pathologies to dementia is critical as neurotherapeutics move toward targeted treatments.

© 2014 American Academy of Neurology.
PMID 25056580  Neurology. 2014 Aug 26;83(9):801-9. doi: 10.1212/WNL.00・・・
著者: I G McKeith, D W Dickson, J Lowe, M Emre, J T O'Brien, H Feldman, J Cummings, J E Duda, C Lippa, E K Perry, D Aarsland, H Arai, C G Ballard, B Boeve, D J Burn, D Costa, T Del Ser, B Dubois, D Galasko, S Gauthier, C G Goetz, E Gomez-Tortosa, G Halliday, L A Hansen, J Hardy, T Iwatsubo, R N Kalaria, D Kaufer, R A Kenny, A Korczyn, K Kosaka, V M Y Lee, A Lees, I Litvan, E Londos, O L Lopez, S Minoshima, Y Mizuno, J A Molina, E B Mukaetova-Ladinska, F Pasquier, R H Perry, J B Schulz, J Q Trojanowski, M Yamada, Consortium on DLB
雑誌名: Neurology. 2005 Dec 27;65(12):1863-72. doi: 10.1212/01.wnl.0000187889.17253.b1. Epub 2005 Oct 19.
Abstract/Text The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

PMID 16237129  Neurology. 2005 Dec 27;65(12):1863-72. doi: 10.1212/01.・・・
著者: Ian McKeith, Jacobo Mintzer, Dag Aarsland, David Burn, Helen Chiu, Jiska Cohen-Mansfield, Dennis Dickson, Bruno Dubois, John E Duda, Howard Feldman, Serge Gauthier, Glenda Halliday, Brian Lawlor, Carol Lippa, Oscar L Lopez, João Carlos Machado, John O'Brien, Jeremy Playfer, Wayne Reid, International Psychogeriatric Association Expert Meeting on DLB
雑誌名: Lancet Neurol. 2004 Jan;3(1):19-28.
Abstract/Text Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

PMID 14693108  Lancet Neurol. 2004 Jan;3(1):19-28.
著者: R C Briel, I G McKeith, W A Barker, Y Hewitt, R H Perry, P G Ince, A F Fairbairn
雑誌名: J Neurol Neurosurg Psychiatry. 1999 Mar;66(3):401-3.
Abstract/Text OBJECTIVES: To evaluate the role of the EEG in the diagnosis of dementia with Lewy bodies (DLB).
METHODS: Standard EEG recordings from 14 patients with DLB confirmed at postmortem were examined and were compared with the records from 11 patients with Alzheimer's disease confirmed at postmortem
RESULTS: Seventeen of the total of 19 records from the patients with DLB were abnormal. Thirteen showed loss of alpha activity as the dominant rhythm and half had slow wave transient activity in the temporal lobe areas. This slow wave transient activity correlated with a clinical history of loss of consciousness. The patients with Alzheimer's disease were less likely to show transient slow waves and tended to have less marked slowing of dominant rhythm.
CONCLUSIONS: The greater slowing of the EEG in DLB than in Alzheimer's disease may be related to a greater loss of choline acetyltransferase found in DLB. Temporal slow wave transients may be a useful diagnostic feature in DLB and may help to explain the transient disturbance of consciousness which is characteristic of the disorder.

PMID 10084544  J Neurol Neurosurg Psychiatry. 1999 Mar;66(3):401-3.
著者: P A Barber, A R Varma, J J Lloyd, B Haworth, J S Snowden, D Neary
雑誌名: Acta Neurol Scand. 2000 Jan;101(1):53-6.
Abstract/Text OBJECTIVES: Dementia with Lewy bodies (DLB) is the second commonest neurodegenerative cause of dementia. While there is consensus on the clinical diagnostic criteria for DLB, the use of EEG to increase the diagnostic sensitivity has not been substantiated.
MATERIAL AND METHODS: We studied the resting EEG findings in 18 consecutive patients with DLB and compared them with a control group of 20 patients with "probable" Alzheimer's disease (AD). We aimed to evaluate the use of EEG in a representative sample of patients with DLB.
RESULTS: All patients with DLB fulfilled accepted clinical criteria for DLB. The DLB group had a more severe dementia than the AD group, as measured by the Mini-Mental State Examination (MMSE) test (DLB mean MMSE 9.4 and AD mean MMSE 17.2) despite a similar duration of overall severity of illness. The EEG was slow in both groups, predominantly in the 4-7 Hz range. Although there was no statistically significant difference in the EEG findings between the DLB and AD groups, there was a correlation between the EEG score and MMSE score (Spearman Rank correlation rs = -0.61, P < 0.001).
CONCLUSION: These findings suggest that although patients with DLB have a more aggressive course than AD, EEG abnormalities do not differ in the 2 groups. However, we believe the EEG provides important supporting diagnostic information in DLB.

PMID 10660153  Acta Neurol Scand. 2000 Jan;101(1):53-6.
著者: T Yamamoto, T Imai
雑誌名: J Neuropathol Exp Neurol. 1988 Sep;47(5):536-48.
Abstract/Text Periodic synchronous discharges were consistently observed in a 68-year-old man with a four-year history of progressive dementia. Pathological examination revealed diffuse atrophy of the brain with remarkable dilatation of the temporal horns. Histologically there were severe changes of Alzheimer's disease and diffuse Lewy bodies (LB), either typical or less distinctive ones without clear halos. Cerebellar LB were also observed in the cerebellum. Four types of abnormal intraneuronal filamentous structures were observed: neurofibrillary tangles, accumulated neurofilaments, thick linear structures studded with ribosome-like dense granules, and fuzzy, thin filaments similar to, but generally wider than, a neurofilament.

PMID 2845002  J Neuropathol Exp Neurol. 1988 Sep;47(5):536-48.
著者: C F Lippa, J E Duda, M Grossman, H I Hurtig, D Aarsland, B F Boeve, D J Brooks, D W Dickson, B Dubois, M Emre, S Fahn, J M Farmer, D Galasko, J E Galvin, C G Goetz, J H Growdon, K A Gwinn-Hardy, J Hardy, P Heutink, T Iwatsubo, K Kosaka, V M-Y Lee, J B Leverenz, E Masliah, I G McKeith, R L Nussbaum, C W Olanow, B M Ravina, A B Singleton, C M Tanner, J Q Trojanowski, Z K Wszolek, DLB/PDD Working Group
雑誌名: Neurology. 2007 Mar 13;68(11):812-9. doi: 10.1212/01.wnl.0000256715.13907.d3.
Abstract/Text For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

PMID 17353469  Neurology. 2007 Mar 13;68(11):812-9. doi: 10.1212/01.wn・・・
著者: Murat Emre, Dag Aarsland, Richard Brown, David J Burn, Charles Duyckaerts, Yoshikino Mizuno, Gerald Anthony Broe, Jeffrey Cummings, Dennis W Dickson, Serge Gauthier, Jennifer Goldman, Christopher Goetz, Amos Korczyn, Andrew Lees, Richard Levy, Irene Litvan, Ian McKeith, Warren Olanow, Werner Poewe, Niall Quinn, Christina Sampaio, Eduardo Tolosa, Bruno Dubois
雑誌名: Mov Disord. 2007 Sep 15;22(12):1689-707; quiz 1837. doi: 10.1002/mds.21507.
Abstract/Text Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

(c) 2007 Movement Disorder Society.
PMID 17542011  Mov Disord. 2007 Sep 15;22(12):1689-707; quiz 1837. doi・・・
著者: Bruno Dubois, David Burn, Christopher Goetz, Dag Aarsland, Richard G Brown, Gerald A Broe, Dennis Dickson, Charles Duyckaerts, Jefferey Cummings, Serge Gauthier, Amos Korczyn, Andrew Lees, Richard Levy, Irene Litvan, Yoshikuni Mizuno, Ian G McKeith, C Warren Olanow, Werner Poewe, Cristina Sampaio, Eduardo Tolosa, Murat Emre
雑誌名: Mov Disord. 2007 Dec;22(16):2314-24. doi: 10.1002/mds.21844.
Abstract/Text A preceding article described the clinical features of Parkinson's disease dementia (PD-D) and proposed clinical diagnostic criteria for "probable" and "possible" PD-D. The main focus of this article is to operationalize the diagnosis of PD-D and to propose practical guidelines based on a two level process depending upon the clinical scenario and the expertise of the evaluator involved in the assessment. Level I is aimed primarily at the clinician with no particular expertise in neuropsychological methods, but who requires a simple, pragmatic set of tests that are not excessively time-consuming. Level I can be used alone or in concert with Level II, which is more suitable when there is the need to specify the pattern and the severity on the dementia of PD-D for clinical monitoring, research studies or pharmacological trials. Level II tests can also be proposed when the diagnosis of PD-D remains uncertain or equivocal at the end of a Level I evaluation. Given the lack of evidence-based standards for some tests when applied in this clinical context, we have tried to make practical and unambiguous recommendations, based upon the available literature and the collective experience of the Task Force. We accept, however, that further validation of certain tests and modifications in the recommended cut off values will be required through future studies.

2007 Movement Disorder Society
PMID 18098298  Mov Disord. 2007 Dec;22(16):2314-24. doi: 10.1002/mds.2・・・
著者: C Ballard, J O'Brien, C M Morris, R Barber, A Swann, D Neill, I McKeith
雑誌名: Int J Geriatr Psychiatry. 2001 May;16(5):499-503.
Abstract/Text BACKGROUND: Little is known about the rate of progression or associations of cognitive impairment in dementia with Lewy bodies (DLB), or the associations of accelerated decline.
METHOD: Dementia patients from a case register were evaluated at baseline and 1 year follow-up using the Cambridge Assessment for Mental Disorders in the Elderly, section B (CAMCOG) and the Mini-Mental State Examination (MMSE) to determine the rate of cognitive decline. Operationalized clinical diagnoses were applied (NINCDS ADRDA for Alzheimer's disease (AD), NINCDS AIRENS for vascular dementia (VaD) and consensus criteria for DLB).
RESULTS: One hundred and ninety-three patients completed annual MMSE schedules (AD, 101; DLB, 64; VaD, 38), of whom 154 completed the CAMCOG. The magnitude of cognitive decline (MMSE, 4-5 points; CAMCOG, 12-14 points) was similar in each of the dementias. The strongest predictor of accelerated cognitive decline in DLB was the apolipoprotein E4 allele (17.5 vs 8.3 points decline on the CAMCOG).
CONCLUSION: Over 1 year, DLB, VaD and AD patients had similar rates of cognitive decline overall. Apolipoprotein E4 may be an important predictor of more rapid decline in DLB.

Copyright 2001 John Wiley & Sons, Ltd
PMID 11376466  Int J Geriatr Psychiatry. 2001 May;16(5):499-503.
著者: T P Armstrong, L A Hansen, D P Salmon, E Masliah, M Pay, J M Kunin, R Katzman
雑誌名: Neurology. 1991 Aug;41(8):1178-80.
Abstract/Text A 65-year-old woman presented with a mild memory impairment, spatial disorientation, and poor task initiation. Progression was rapid over 3 months. She developed severe apathy, delusions, extrapyramidal features, and psychometrically quantified cognitive deterioration. Her brain showed many neocortical neuritic plaques and neurofibrillary tangles along with neocortical and brainstem Lewy bodies and temporal lobe spongiform vacuolization. This case is the most rapid deterioration documented of a patient with Alzheimer's disease and Lewy bodies.

PMID 1714056  Neurology. 1991 Aug;41(8):1178-80.
著者: O L Lopez, S Wisniewski, R L Hamilton, J T Becker, D I Kaufer, S T DeKosky
雑誌名: Neurology. 2000 May 9;54(9):1774-9.
Abstract/Text OBJECTIVE: To examine the differences in the pattern of progression between AD and AD with Lewy bodies (AD+LB).
METHODS: The authors examined predictors of functional and cognitive disability, institutionalization, and death, as well as time to the development of psychosis (e.g., delusions, hallucinations), extrapyramidal signs (EPS), diurnal hypersomnia, and depression in 185 patients with definite AD and 60 with autopsy-confirmed AD+LB. In addition, they analyzed a selected group of patients who did not have comorbid systemic or CNS disease that may have affected progression of the disease (AD = 98 versus AD+LB = 44). The mean follow-up was 58.91 +/- 35.2 months.
RESULTS: All cases: Patients with AD+LB had faster time to the development of EPS and diurnal hypersomnia, but not to the development of psychosis or depression. The rate of cognitive and functional decline, time to institutionalization, and physical survival was not different between AD+LB and AD. Selected cases: Patients with AD+LB developed earlier EPS and diurnal hypersomnia than AD patients, and there was a trend to develop earlier major depression, but no differences were noted in time to psychosis. Patients with AD+LB had a faster time to institutionalization than those with AD. The rate of cognitive and functional decline and physical survival was not different between AD+LB and AD in these selected cases.
CONCLUSION: Patients with AD+LB can develop EPS and diurnal hypersomnia earlier and have faster time to institutionalization than those with AD alone, but cognitive and functional decline and physical survival are similar between these two entities.

PMID 10802783  Neurology. 2000 May 9;54(9):1774-9.
著者: S P Cercy, F W Bylsma
雑誌名: J Int Neuropsychol Soc. 1997 Mar;3(2):179-94.
Abstract/Text Researchers disagree as to whether Lewy body disease (LBD) constitutes a variant of Alzheimer's (AD) or Parkinson's disease (PD), or alternatively, whether it is an independent disease process. The neuropathological, genetic, and clinical characteristics of LBD are reviewed and compared to those of AD and PD. Data for 150 cases of LBD reported in the literature were compiled and grouped according to neuropathological status. Patients with pure LBD (with limited or no concurrent AD pathology) tend to present at a younger age with extrapyramidal signs followed by dementia, whereas patients with mixed LBD-AD (concurrent LB and AD pathology) are somewhat older and tend to present with dementia. The cognitive profile of LBD patients, and the relationships among LBD, AD, and PD remain unclear due to methodological limitations and the paucity of studies comparing the groups directly.

PMID 9126859  J Int Neuropsychol Soc. 1997 Mar;3(2):179-94.
著者: Z Walker, R L Allen, S Shergill, E Mullan, C L Katona
雑誌名: Int J Geriatr Psychiatry. 2000 Mar;15(3):267-73.
Abstract/Text The majority of information available on the prognosis of dementia with Lewy bodies (DLB) is based on retrospective data from autopsy series, which are subject to selection bias due to the specific reasons patients are referred for post-mortem studies. The earlier studies comparing DLB patients with patients with Alzheimer's disease (AD) suggest that the mean duration of illness is shorter in DLB patients than in patients with AD. However, more recent studies have not observed significant differences between DLB and AD in age of onset, age at death or duration of illness. We report a 3 year follow-up of a cohort of 114 consecutive patients with dementia, referred to an old age psychiatric service and diagnosed using ICD 10 criteria and the McKeith and Byrne DLB criteria. The case notes of all patients were reviewed to determine the date of onset of symptoms and the date of first presentation to the psychiatric services. Information about outcome was gathered from case notes, hospital files and general practitioner (GP) records. Of the original sample of 114 patients, 106 could be traced. Sixty-four had died and 42 were still alive at the time of the follow-up. Thirty-two patients had originally been assigned the diagnosis of DLB, 43 the diagnosis of AD, 31 vascular dementia and other diagnoses. There were no differences between the AD and DLB group in age at onset, age at death or survival. We have not found any evidence that the prognosis of clinically diagnosed DLB patients is worse than that of patients with a clinical diagnosis of AD.

PMID 10713586  Int J Geriatr Psychiatry. 2000 Mar;15(3):267-73.
著者: Philip S Wang, Sebastian Schneeweiss, Jerry Avorn, Michael A Fischer, Helen Mogun, Daniel H Solomon, M Alan Brookhart
雑誌名: N Engl J Med. 2005 Dec 1;353(22):2335-41. doi: 10.1056/NEJMoa052827.
Abstract/Text BACKGROUND: Recently, the Food and Drug Administration (FDA) issued an advisory stating that atypical antipsychotic medications increase mortality among elderly patients. However, the advisory did not apply to conventional antipsychotic medications; the risk of death with these older agents is not known.
METHODS: We conducted a retrospective cohort study involving 22,890 patients 65 years of age or older who had drug insurance benefits in Pennsylvania and who began receiving a conventional or atypical antipsychotic medication between 1994 and 2003. Analyses of mortality rates and Cox proportional-hazards models were used to compare the risk of death within 180 days, less than 40 days, 40 to 79 days, and 80 to 180 days after the initiation of therapy with an antipsychotic medication. We controlled for potential confounding variables with the use of traditional multivariate Cox models, propensity-score adjustments, and an instrumental-variable analysis.
RESULTS: Conventional antipsychotic medications were associated with a significantly higher adjusted risk of death than were atypical antipsychotic medications at all intervals studied (< or =180 days: relative risk, 1.37; 95 percent confidence interval, 1.27 to 1.49; <40 days: relative risk, 1.56; 95 percent confidence interval, 1.37 to 1.78; 40 to 79 days: relative risk, 1.37; 95 percent confidence interval, 1.19 to 1.59; and 80 to 180 days: relative risk, 1.27; 95 percent confidence interval, 1.14 to 1.41) and in all subgroups defined according to the presence or absence of dementia or nursing home residency. The greatest increases in risk occurred soon after therapy was initiated and with higher dosages of conventional antipsychotic medications. Increased risks associated with conventional as compared with atypical antipsychotic medications persisted in confirmatory analyses performed with the use of propensity-score adjustment and instrumental-variable estimation.
CONCLUSIONS: If confirmed, these results suggest that conventional antipsychotic medications are at least as likely as atypical agents to increase the risk of death among elderly persons and that conventional drugs should not be used to replace atypical agents discontinued in response to the FDA warning.

Copyright 2005 Massachusetts Medical Society.
PMID 16319382  N Engl J Med. 2005 Dec 1;353(22):2335-41. doi: 10.1056/・・・
著者: Lon S Schneider, Karen S Dagerman, Philip Insel
雑誌名: JAMA. 2005 Oct 19;294(15):1934-43. doi: 10.1001/jama.294.15.1934.
Abstract/Text CONTEXT: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use.
OBJECTIVE: To assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia.
DATA SOURCES: MEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.
STUDY SELECTION: Published and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors.
DATA EXTRACTION: Trials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer.
DATA SYNTHESIS: Fifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.
CONCLUSIONS: Atypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed.

PMID 16234500  JAMA. 2005 Oct 19;294(15):1934-43. doi: 10.1001/jama.29・・・
著者: Sebastian Schneeweiss, Soko Setoguchi, Alan Brookhart, Colin Dormuth, Philip S Wang
雑誌名: CMAJ. 2007 Feb 27;176(5):627-32. doi: 10.1503/cmaj.061250.
Abstract/Text BACKGROUND: Public health advisories have warned that the use of atypical antipsychotic medications increases the risk of death among elderly patients. We assessed the short-term mortality in a population-based cohort of elderly people in British Columbia who were prescribed conventional and atypical antipsychotic medications.
METHODS: We used linked health care utilization data of all BC residents to identify a cohort of people aged 65 years and older who began taking antipsychotic medications between January 1996 and December 2004 and were free of cancer. We compared the 180-day all-cause mortality between residents taking conventional antipsychotic medications and those taking atypical antipsychotic medications.
RESULTS: Of 37 241 elderly people in the study cohort, 12 882 were prescribed a conventional antipsychotic medication and 24 359 an atypical formulation. Within the first 180 days of use, 1822 patients (14.1%) in the conventional drug group died, compared with 2337 (9.6%) in the atypical drug group (mortality ratio 1.47, 95% confidence interval [CI] 1.39-1.56). Multivariable adjustment resulted in a 180-day mortality ratio of 1.32 (1.23-1.42). In comparison with risperidone, haloperidol was associated with the greatest increase in mortality (mortality ratio 2.14, 95% CI 1.86-2.45) and loxapine the lowest (mortality ratio 1.29, 95% CI 1.19-1.40). The greatest increase in mortality occurred among people taking higher (above median) doses of conventional antipsychotic medications (mortality ratio 1.67, 95% CI 1.50-1.86) and during the first 40 days after the start of drug therapy (mortality ratio 1.60, 95% CI 1.42-1.80). Results were confirmed in propensity score analyses and instrumental variable estimation, minimizing residual confounding.
INTERPRETATION: Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greater than the risk of death associated with atypical antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients.

PMID 17325327  CMAJ. 2007 Feb 27;176(5):627-32. doi: 10.1503/cmaj.0612・・・
著者: Sudeep S Gill, Susan E Bronskill, Sharon-Lise T Normand, Geoffrey M Anderson, Kathy Sykora, Kelvin Lam, Chaim M Bell, Philip E Lee, Hadas D Fischer, Nathan Herrmann, Jerry H Gurwitz, Paula A Rochon
雑誌名: Ann Intern Med. 2007 Jun 5;146(11):775-86.
Abstract/Text BACKGROUND: Antipsychotic drugs are widely used to manage behavioral and psychological symptoms in dementia despite concerns about their safety.
OBJECTIVE: To examine the association between treatment with antipsychotics (both conventional and atypical) and all-cause mortality.
DESIGN: Population-based, retrospective cohort study.
SETTING: Ontario, Canada.
PATIENTS: Older adults with dementia who were followed between 1 April 1997 and 31 March 2003.
MEASUREMENTS: The risk for death was determined at 30, 60, 120, and 180 days after the initial dispensing of antipsychotic medication. Two pairwise comparisons were made: atypical versus no antipsychotic use and conventional versus atypical antipsychotic use. Groups were stratified by place of residence (community or long-term care). Propensity score matching was used to adjust for differences in baseline health status.
RESULTS: A total of 27,259 matched pairs were identified. New use of atypical antipsychotics was associated with a statistically significant increase in the risk for death at 30 days compared with nonuse in both the community-dwelling cohort (adjusted hazard ratio, 1.31 [95% CI, 1.02 to 1.70]; absolute risk difference, 0.2 percentage point) and the long-term care cohort (adjusted hazard ratio, 1.55 [CI, 1.15 to 2.07]; absolute risk difference, 1.2 percentage points). Excess risk seemed to persist to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic use, conventional antipsychotic use was associated with a higher risk for death at all time points. Sensitivity analysis revealed that unmeasured confounders that increase the risk for death could diminish or eliminate the observed associations.
LIMITATIONS: Information on causes of death was not available. Many patients did not continue their initial treatments after 1 month of therapy. Unmeasured confounders could affect associations.
CONCLUSIONS: Atypical antipsychotic use is associated with an increased risk for death compared with nonuse among older adults with dementia. The risk for death may be greater with conventional antipsychotics than with atypical antipsychotics.

PMID 17548409  Ann Intern Med. 2007 Jun 5;146(11):775-86.
著者: P Tiraboschi, L A Hansen, M Alford, M N Sabbagh, B Schoos, E Masliah, L J Thal, J Corey-Bloom
雑誌名: Neurology. 2000 Jan 25;54(2):407-11.
Abstract/Text OBJECTIVE: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype.
BACKGROUND: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear.
METHODS: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined.
RESULTS: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8) compared to NC (255.4 +/- 134.6; p < 0.001) and AD (122.6 +/- 78.9; p < 0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7; AD: 322.8 +/- 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 +/- 360.3; p < 0.001). The epsilon4 allele dosage did not influence midfrontal ChAT activity in LBV.
CONCLUSION: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.

PMID 10668703  Neurology. 2000 Jan 25;54(2):407-11.
著者: Pietro Tiraboschi, Larry A Hansen, Michael Alford, Annette Merdes, Eliezer Masliah, Leon J Thal, Jody Corey-Bloom
雑誌名: Arch Gen Psychiatry. 2002 Oct;59(10):946-51.
Abstract/Text BACKGROUND: Reductions in cholinergic function occur in Alzheimer disease (AD) and dementia with Lewy bodies and correlate with cognitive decline. However, whether such alterations appear in early-stage disease is unclear.
OBJECTIVE: To examine the timing of cholinergic deficits in AD and dementia with Lewy bodies.
METHODS: Autopsy series of 89 patients with AD and 50 patients with the Lewy body variant of AD (LBV). Stage of disease was stratified according to results of the last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. We analyzed choline acetyltransferase (ChAT) activity in the midfrontal, superior temporal, and inferior parietal cortices.
RESULTS: Although compared with a normal control group ChAT activity was decreased in the AD and LBV cohorts, ChAT activity reduction for the LBV cohort was much greater. Moreover, although the decline in ChAT activity in the AD cohort compared with the normal control group was significant only for patients in later stages of the illness, the decline in the LBV cohort was significant for those who died with mild-stage disease. When less impaired patients in each cohort (MMSE, > or = 10) underwent separate analysis, the relationship of ChAT activity with the MMSE score was strong and significant for the LBV cohort alone.
CONCLUSIONS: Although cholinergic deficits are seen in both AD and LBV, loss of ChAT activity is less severe and occurs later in the clinical course of AD. Conversely, in LBV, loss of ChAT activity is already prominent in the earliest stages of the illness, suggesting that cholinergic replacement therapy may be more effective in LBV than in AD, especially in mild-stage disease.

PMID 12365882  Arch Gen Psychiatry. 2002 Oct;59(10):946-51.
著者: Martine Simard, Robert van Reekum
雑誌名: J Neuropsychiatry Clin Neurosci. 2004 Fall;16(4):409-25. doi: 10.1176/appi.neuropsych.16.4.409.
Abstract/Text Dementia with Lewy bodies (DLB) is a common cause of dementia with effects on cognition, mood, behavior, and function. Changes in the acetylcholine system have been reported in brains of patients with DLB, which provides a rationale for trials of acetylcholinesterase inhibitors in DLB. This review includes all English-language publications found via Medline and related to the efficacy and/or safety of these compounds in DLB. Preliminary data suggest that these compounds may be efficacious in DLB and that future randomized clinical trials are strongly needed. Methodological limitations of the existing data include small sample sizes, and the paucity of standardized psychometric measures.

PMID 15616167  J Neuropsychiatry Clin Neurosci. 2004 Fall;16(4):409-25・・・
著者: Elise Rowan, Ian G McKeith, Brian K Saxby, John T O'Brien, David Burn, Urs Mosimann, Jane Newby, Sarah Daniel, Jonathan Sanders, Keith Wesnes
雑誌名: Dement Geriatr Cogn Disord. 2007;23(3):161-7. doi: 10.1159/000098335. Epub 2006 Dec 28.
Abstract/Text BACKGROUND: We examined attention-enhancing effects of the cholinesterase inhibitor donepezil in Dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) by means of open label study.
METHODS: 22 DLBs and 23 PDDs were assessed over 20 weeks using the Cognitive Drug Research Computerized Attentional Tasks. We examined how much closer our patients moved towards being normal for their age by comparing them to a non-demented elderly control sample (n = 183, aged 71-75 years).
RESULTS: Donepezil treatment improved power of attention, continuity of attention and reaction time variability. The deficit in responses was moved towards normal by 38 and 56% for power of attention and 22 and 10% for continuity of attention in PDD and DLB, respectively.
CONCLUSIONS: Improvements in attention were found with donepezil in PDD and DLB.

PMID 17192712  Dement Geriatr Cogn Disord. 2007;23(3):161-7. doi: 10.1・・・
著者: Sanjeet Pakrasi, Alan Thomas, Urs P Mosimann, David A Cousins, Debbie Lett, David J Burn, John T O'Brien, Ian G McKeith
雑誌名: Int J Geriatr Psychiatry. 2006 Aug;21(8):719-21. doi: 10.1002/gps.1547.
Abstract/Text INTRODUCTION: There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB.
METHOD: We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms.
RESULTS: The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment.
CONCLUSION: Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

PMID 16858742  Int J Geriatr Psychiatry. 2006 Aug;21(8):719-21. doi: 1・・・
著者: Satoru Mori, Etsuro Mori, Eizo Iseki, Kenji Kosaka
雑誌名: Psychiatry Clin Neurosci. 2006 Apr;60(2):190-5. doi: 10.1111/j.1440-1819.2006.01485.x.
Abstract/Text The objectives of the present study were first to determine the feasibility of conducting a randomized clinical trial of 5 mg/day donepezil in patients with mild to moderate dementia with Lewy bodies (DLB) and second, to obtain preliminary data of possible intervention effects. Twelve patients with probable DLB were evaluated at weeks 4, 8, and 12 using modified Neuropsychiatric Inventory (NPI) with an extra domain to additionally evaluate fluctuation in cognitive functions (NPI-11); the Japanese version of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog); and the Unified Parkinson's Disease Rating Scale (UPDRS). The NPI-11 scores were significantly improved at weeks 8 and 12 compared with baseline. Despite a significant improvement in ADAS-J-cog at week 4, no more improvement was noted thereafter. Deterioration was not noted in UPDRS scores. Donepezil is expected to be therapeutically useful and safe in treating DLB patients, indicating marked improvements in behavioral and psychological symptoms of dementia (BPSD) rather than in cognitive deficit, without deteriorating parkinsonism.

PMID 16594943  Psychiatry Clin Neurosci. 2006 Apr;60(2):190-5. doi: 10・・・
著者: Alan J Thomas, David J Burn, Elise N Rowan, Elizabeth Littlewood, Jane Newby, David Cousins, Sanjeet Pakrasi, Jonathan Richardson, Jonathan Sanders, Ian G McKeith
雑誌名: Int J Geriatr Psychiatry. 2005 Oct;20(10):938-44. doi: 10.1002/gps.1381.
Abstract/Text BACKGROUND: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) overlap in phenomenology and neurochemical deficits. We hypothesised they would not differ in their response to the cholinesterase inhibitor donepezil.
METHODS: We recruited 70 subjects, 30 DLB and 40 PDD, in an open label study to compare the efficacy of donepezil in these two patient groups. They were assessed at baseline, 4, 12 and 20 weeks. The main outcome measures were the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) and motor sub-section of the Unified Parkinson's Disease Rating Scale (UPDRS III).
RESULTS: PDD patients were younger than DLB and had more severe parkinsonism at baseline. The groups were similar on all other variables of interest. By 20 weeks the mean MMSE score increased by 3.9 points in the DLB group and by 3.2 points in PDD. The mean NPI score reduced by 14.6 points for DLB and 12.0 points for PDD. These treatment effects were all significant compared to baseline (p < 0.001) but there were no significant between-group treatment differences (MMSE p = 0.56, NPI p = 0.39). UPDRS III motor scores did not change significantly from baseline values in either group. Although adverse effects were common (69%) they were usually mild and 64 patients (91%) completed the study. The four patients who did withdraw with adverse effects all had a PDD diagnosis.
CONCLUSIONS: Donepezil produced similar improvements in cognition and behaviour in DLB and PDD. This supports the hypothesis that the two disorders are closely related clinically and neurobiologically. Larger scale, placebo controlled clinical trials are needed to provide an evidence base to guide the clinical use of cholinesterase inhibitors in Lewy body disease.

Copyright (c) 2005 John Wiley & Sons, Ltd.
PMID 16163744  Int J Geriatr Psychiatry. 2005 Oct;20(10):938-44. doi: ・・・
著者: W Samuel, M Caligiuri, D Galasko, J Lacro, M Marini, F S McClure, K Warren, D V Jeste
雑誌名: Int J Geriatr Psychiatry. 2000 Sep;15(9):794-802.
Abstract/Text In several retrospective post-mortem studies, patients meeting clinical criteria for Alzheimer's disease (AD) who gained the greatest cognitive benefit from treatment with an acetylcholinesterase (AChE) inhibitor were found to have neocortical Lewy bodies accompanying classical AD neuropathology. This 'dementia with Lewy bodies' (DLB) subtype manifests both parkinsonian and psychopathologic features that set it apart from 'pure' AD (hereafter called AD). In the present preliminary study, 16 dementia patients were prospectively categorized as having DLB versus AD. Subjects were also categorized according to their profile on surface electromyographic (EMG) measures demonstrated in prior work to be analogues of clinically observed parkinsonian extrapyramidal signs (EPS). All patients were prescribed the AChE inhibitor donepezil (5 mg per day). At baseline and at 6 months, patients underwent cognitive testing with the Mini-Mental State Examination (MMSE) while caregivers assessed their psychopathologic status using the Behavioral Symptoms in Alzheimer's Disease (BEHAVE-AD) scale. The tester was blinded to the AD versus DLB classification of the patients. AD cases (N=12) had only a slight increase in cognitive scores, while DLB patients' (N=4) mean MMSE scores increased to a significantly greater degree. Furthermore, patients categorized by EMG as EPS positive (N=8) attained an increase in their mean MMSE score from baseline to 6 months that differed significantly from a decline in MMSE observed among their EPS negative (N=4) counterparts. For all subjects, an increase in MMSE scores across 6 months of treatment correlated with a decline in BEHAVE-AD scores.

Copyright 2000 John Wiley & Sons, Ltd.
PMID 10984725  Int J Geriatr Psychiatry. 2000 Sep;15(9):794-802.
著者: C Shea, C MacKnight, K Rockwood
雑誌名: Int Psychogeriatr. 1998 Sep;10(3):229-38.
Abstract/Text Dementia with Lewy bodies (DLB) is common. Symptomatic treatment can be difficult. We reviewed nine consecutive patients with DLB (mean age 77.5 [range 67 to 84] years; seven men and two women; mean duration of disease 3.7 [range 1.5 to 8.0] years) who had been treated with donepezil. Each initially received 2.5 to 5 mg per day of donepezil, and was stabilized on 5 mg per day. Donepezil was increased to 10 mg per day in five patients. The mean observation period was 12 (range 8 to 24) weeks. Target symptoms included cognition, hallucinations, parkinsonism, and functional abilities. By both cognitive testing and family reports, cognition improved in seven of nine patients, remained the same in one of nine, and fluctuated in one of nine (mean Mini-Mental State Examination change 4.4 +/- 6.3 points). Function was improved or maintained in six of nine patients and fluctuated in two of nine. Hallucinations initially worsened, then fluctuated in one patient, but improvement in frequency, duration, and content was reported in eight of nine cases. In three of nine patients, treatment with donepezil resulted in worsening of parkinsonism, which in each case responded to levodopa/carbidopa. Treatment of DLB patients with donepezil for 12 weeks most commonly improved hallucinations, and sometimes improved cognition and overall function. Treatment with donepezil was sometimes associated with worse parkinsonism.

PMID 9785144  Int Psychogeriatr. 1998 Sep;10(3):229-38.
著者: Manabu Ikeda, Etsuro Mori, Kenji Kosaka, Eizo Iseki, Mamoru Hashimoto, Noriyuki Matsukawa, Kazutaka Matsuo, Masaki Nakagawa, Donepezil-DLB Study Investigators
雑誌名: Dement Geriatr Cogn Disord. 2013;36(3-4):229-41. doi: 10.1159/000351672. Epub 2013 Aug 15.
Abstract/Text BACKGROUND/AIMS: To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB).
METHODS: This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout.
RESULTS: In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear.
CONCLUSION: The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks.

© 2013 S. Karger AG, Basel.
PMID 23949147  Dement Geriatr Cogn Disord. 2013;36(3-4):229-41. doi: 1・・・
著者: J Grace, S Daniel, T Stevens, K K Shankar, Z Walker, E J Byrne, S Butler, D Wilkinson, J Woolford, J Waite, I G McKeith
雑誌名: Int Psychogeriatr. 2001 Jun;13(2):199-205.
Abstract/Text Patients with dementia with Lewy bodies (DLB) have progressive deficits in cognition, parkinsonism, and neuropsychiatric symptoms. Cholinesterase inhibitors have been used to ameliorate cognitive decline and neuropsychiatric symptoms in short-term trials. In this study, patients with DLB were treated with rivastigmine up to 96 weeks. Improvement from baseline was seen in cognitive function as measured by the Mini-Mental State Examination (MMSE), and neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) over the first 24 weeks of treatment. By 96 weeks, neither the MMSE scores nor the NPI scores were significantly worse than at baseline.

PMID 11495394  Int Psychogeriatr. 2001 Jun;13(2):199-205.
著者: T Del Ser, I McKeith, R Anand, A Cicin-Sain, R Ferrara, R Spiegel
雑誌名: Int J Geriatr Psychiatry. 2000 Nov;15(11):1034-45.
Abstract/Text OBJECTIVES: To describe the baseline demographic, neuropsychiatric and neurological data of a large selected clinical sample of patients with dementia with Lewy Bodies (DLB) from an international multicentre trial with rivastigmine. To examine the usefulness of the Consensus Criteria for the diagnosis of DLB in different countries.
METHODS: Seventeen centres from Spain, the UK and Italy recruited patients diagnosed clinically as probable DLB according to recent Consensus Criteria (McKeith et al., 1996). A standard clinical protocol including inclusion/exclusion criteria, collection of demographic and medical data, cognitive (Mini Mental State Examination: MMSE), motor (Unified Parkinson's Disease Rating Scale: UPDRS) and neuropsychiatric (Neuropsychiatric Inventory: NPI) examinations, was applied after obtaining informed consent. Data were summarised and compared across countries with uni- and multivariate analyses.
RESULTS: One hundred and twenty patients were recruited: 56.7% males, mean (SD) age 73.9 (6.4) years, range 57 - 87 years. Sixty percent fulfilled all three core diagnostic features of DLB, and 40% only two ('parkinsonism' 92.4%, 'cognitive fluctuations' 89.1%, 'visual hallucinations' 77.3%). 'Systematised delusions' (46%) and 'repeated falls' (42%) were the most frequent supportive diagnostic features. There were no differences across countries in demographic, diagnostic or clinical features. Patients showed a wide range of psychopathology which was weakly correlated with cognitive impairment. Some mild extrapyramidal signs (EPS) were observed in most patients.
CONCLUSIONS: The Consensus Criteria for DLB can be consistently applied across many different sites for multicentre studies. 'Parkinsonism' and 'cognitive fluctuations' as core features and 'systematised delusions' and 'repeated falls' as supportive features are the most frequent diagnostic clues. Neuropsychiatric disturbances, in particular apathy, delusions, hallucinations and anxiety, and mild symmetric EPS are frequent in DLB and are only related weakly to cognitive impairment.

Copyright 2000 John Wiley & Sons, Ltd.
PMID 11113984  Int J Geriatr Psychiatry. 2000 Nov;15(11):1034-45.
著者: I G McKeith, J B Grace, Z Walker, E J Byrne, D Wilkinson, T Stevens, E K Perry
雑誌名: Int J Geriatr Psychiatry. 2000 May;15(5):387-92.
Abstract/Text The objective of this study was to assess the tolerability and efficacy of rivastigmine in a group of patients with probable dementia with Lewy bodies (DLB), using an open label study. Open label treatment was with rivastigmine up to maximum tolerated dose (mean 9.6 mg daily, range 3-12 mg). Eleven patients with DLB, mean age 78.5 years, were treated with this cholinesterase inhibitor. After 12 weeks of treatment, mean Neuropsychiatric Inventory scores fell by 73% for delusions, 63% for apathy, 45% for agitation and 27% for hallucinations. Five of the patients (45%) experienced very significant clinical improvements that had not been achieved with other treatments, including low dose neuroleptics. Medication was well tolerated and parkinsonian symptoms tended to improve. Cholinesterase inhibition may be a safe and effective alternative to neuroleptic treatment in DLB. Such effects may also prove to be applicable to the management of neuropsychiatric symptoms in Parkinson's disease and Alzheimer's disease.

Copyright 2000 John Wiley & Sons, Ltd.
PMID 10822236  Int J Geriatr Psychiatry. 2000 May;15(5):387-92.
著者: I McKeith, T Del Ser, P Spano, M Emre, K Wesnes, R Anand, A Cicin-Sain, R Ferrara, R Spiegel
雑誌名: Lancet. 2000 Dec 16;356(9247):2031-6. doi: 10.1016/S0140-6736(00)03399-7.
Abstract/Text BACKGROUND: Dementia with Lewy bodies is a common form of dementia in the elderly, characterised clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other neuropsychiatric features. Neuroleptic medication can provoke severe sensitivity reactions in patients with dementia of this type. Many deficits in cholinergic neurotransmission are seen in the brain of patients with Lewy-body dementia; therefore, drugs enhancing central cholinergic function represent a rationally-based therapeutic approach to this disorder. Rivastigmine, a cholinesterase inhibitor, was tested in a group of clinically characterised patients with Lewy-body dementia.
METHODS: A placebo-controlled, double-blind, multicentre study was done in 120 patients with Lewy-body dementia from the UK, Spain, and Italy. Individuals were given up to 12 mg rivastigmine daily or placebo for 20 weeks, followed by 3 weeks rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis.
FINDINGS: Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine (37, 63%), than on placebo (18, 30%), showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks with a substantial attentional component. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. After drug discontinuation differences between rivastigmine and placebo tended to disappear. Known adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) were seen more frequently with rivastigmine than with placebo, but safety and tolerability of the drug in these mostly multimorbid patients were judged acceptable.
INTERPRETATION: Rivastigmine 6-12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually.

PMID 11145488  Lancet. 2000 Dec 16;356(9247):2031-6. doi: 10.1016/S014・・・
著者: Keith Edwards, Donald Royall, Linda Hershey, David Lichter, Ann Hake, Martin Farlow, Florence Pasquier, Stewart Johnson
雑誌名: Dement Geriatr Cogn Disord. 2007;23(6):401-5. doi: 10.1159/000101512. Epub 2007 Apr 3.
Abstract/Text BACKGROUND: Dementia with Lewy bodies (DLB) is a common dementia of the elderly. A significant cholinergic deficit has been demonstrated that may be responsive to treatment by cholinesterase inhibitors (ChEIs).
METHODS: A 24-week, open-label study was designed to assess the efficacy and safety of a ChEI, galantamine, in 50 patients with DLB.
RESULTS: This study showed beneficial effects with galantamine in 2 of the 3 primary efficacy parameters. The scores on the Neuropsychiatric Inventory (NPI-12) improved by 8.24 points from baseline (p = 0.01) especially in visual hallucinations and nighttime behaviors (p = 0.004). The scores on the Clinician's Global Impression of Change improved by 0.5 points from baseline (p = 0.01). The third primary efficacy parameter, the Cognitive Drug Research Computerized Cognitive Assessment System, was unchanged from baseline. Adverse events were generally mild and transient.
CONCLUSION: Galantamine appears to be an effective and safe therapy for patients with DLB.

PMID 17409748  Dement Geriatr Cogn Disord. 2007;23(6):401-5. doi: 10.1・・・
著者: Keith R Edwards, Linda Hershey, Laura Wray, Edward M Bednarczyk, David Lichter, Martin Farlow, Stewart Johnson
雑誌名: Dement Geriatr Cogn Disord. 2004;17 Suppl 1:40-8. doi: 10.1159/000074681.
Abstract/Text Observations on the neurochemistry of dementia with Lewy bodies (DLB) have suggested that cholinesterase inhibitors (ChEIs) might be beneficial in treating some clinical symptoms of DLB. A 24-week, multicenter open-label study was designed to assess the safety and efficacy of the ChEI galantamine in patients with DLB, and an interim analysis of results was performed at 12 weeks. Efficacy analyses were performed on data from 25 patients. Scores on the Neuropsychiatric Inventory (NPI-12) improved (decreased) by 7.52 points over the 12 weeks (marginally significant, p = 0.061). NPI-12 scores decreased by half in 12 of the 25 patients. Highly significant improvement was observed in scores on the NPI-4 subscale (delusions, hallucinations, apathy, and depression: p = 0.003). Scores on the Clinician's Global Impression of Change (CGIC) improved by 0.95 points (significant, p = 0.02). Improvements also were found in secondary efficacy variables, including cognitive, functional, activities of daily living, sleep and confusion assessments. Motor scores, as measured by the UPDRS motor subscale, showed mild improvement, which demonstrates that galantamine has no adverse effect on parkinsonian symptoms. Adverse events generally were transient and of mild-to-moderate intensity. Two of the 25 patients discontinued galantamine because of nausea and anorexia. One serious adverse event was recorded, but it was judged to be unrelated to the study medication.

Copyright 2004 S. Karger AG, Basel
PMID 14676468  Dement Geriatr Cogn Disord. 2004;17 Suppl 1:40-8. doi: ・・・
著者: Victoria Larsson, Dag Aarsland, Clive Ballard, Lennart Minthon, Elisabet Londos
雑誌名: Int J Geriatr Psychiatry. 2010 Oct;25(10):1030-8. doi: 10.1002/gps.2506.
Abstract/Text OBJECTIVE: Two common and characteristic sleep disturbances have been described in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD); excessive daytime sleepiness and REM sleep behaviour disorder (RBD). This study is an analysis of a secondary outcome measure of a larger study already reported, aimed to determine whether memantine has an effect on the sleep disturbances in DLB and PDD patients.
METHODS: Patients with DLB or PDD were included in a placebo-controlled, randomised controlled study of memantine (20 mg per day) for 24 weeks. The Stavanger Sleep Questionnaire and the Epworth Sleepiness Scale were used to evaluate the effect on sleep disturbances.
RESULTS: Forty two patients started treatment; 20 with memantine and 22 with placebo. The primary analysis was the comparison of change between the two groups during a 24-week period, using the modified ITT population (last observation carried forward). At 24 weeks, patients treated with memantine were less physically active during sleep while patients in the placebo group worsened. Mean difference between the groups (0.5 [0.05-0.90]) was significant (p = 0.006). No significant change was observed in severity of excessive daytime sleepiness.
CONCLUSIONS: Memantine decreases probable REM sleep behaviour disorder in patients with DLB and PDD. Both diagnostic groups contributed equally to the outcome.

Copyright © 2010 John Wiley & Sons, Ltd.
PMID 20872929  Int J Geriatr Psychiatry. 2010 Oct;25(10):1030-8. doi: ・・・
著者: Murat Emre, Magda Tsolaki, Ubaldo Bonuccelli, Alain Destée, Eduardo Tolosa, Alexandra Kutzelnigg, Andrés Ceballos-Baumann, Slobodan Zdravkovic, Anna Bladström, Roy Jones, 11018 Study Investigators
雑誌名: Lancet Neurol. 2010 Oct;9(10):969-77. doi: 10.1016/S1474-4422(10)70194-0. Epub 2010 Aug 20.
Abstract/Text BACKGROUND: Previous studies have suggested that patients with Lewy-body-related dementias might benefit from treatment with the N-methyl D-aspartate receptor antagonist memantine, but further data are needed. Therefore, the efficacy and safety of memantine were investigated in patients with mild to moderate Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB).
METHODS: Patients (≥50 years of age) with mild to moderate PDD or DLB were recruited from 30 specialist centres in Austria, France, Germany, the UK, Greece, Italy, Spain, and Turkey. They were randomly assigned to placebo or memantine (20 mg per day) according to a computer-generated list. Patients and all physicians who had contact with them were masked to treatment assignment. No primary endpoint was defined. Safety analyses were done for all patients who took at least one dose of memantine or placebo, and efficacy analyses were done for all patients who had at least one valid postbaseline assessment. This trial is registered with ClinicalTrials.gov, number NCT00855686.
FINDINGS: Of the 199 patients randomly assigned to treatment, 34 with DLB and 62 with PDD were given memantine, and 41 with DLB and 58 with PDD were given placebo. 159 (80%) patients completed the study: 80 in the memantine group and 79 in the placebo group. 93 patients treated with memantine and 97 patients treated with placebo were included in the efficacy analysis. At week 24, patients with DLB who received memantine showed greater improvement according to Alzheimer's disease cooperative study (ADCS)-clinical global impression of change scores than did those who received placebo (mean change from baseline 3·3 vs 3·9, respectively, difference -0·6 [95% CI -1·2 to -0·1]; p=0·023). No significant differences were noted between the two treatments in patients with PDD (3·6 with memantine vs 3·8 with placebo, -0·1 [-0·6 to 0·3]; p=0·576) or in the total population (3·5 with memantine vs 3·8 with placebo, -0·3 [-0·7 to 0·1]; p=0·120). Neuropsychiatric-inventory scores showed significantly greater improvement in the memantine group than in the placebo group (-4·3 vs 1·7, respectively, -5·9 [-11·6 to -0·2]; p=0·041) in patients with DLB, but not in those with PDD (-1·6 vs -0·1, respectively, -1·4 [-5·9 to 3·0]; p=0·522) or in the total patient population (-2·6 vs 0·4, respectively, -2·9 [-6·3 to 0·5]; p=0·092). In most of the cognitive test scores, ADCS-activities of daily living, and Zarit caregiver burden scores, there were no significant differences between the two treatment groups in any of the study populations. The incidence of adverse events and number of discontinuations due to adverse events were similar in the two groups. The most common serious adverse events were stroke (n=3 in memantine group), falls (n=2 in memantine group; n=1 in placebo group), and worsening of dementia (n=2 in memantine group).
INTERPRETATION: Memantine seems to improve global clinical status and behavioural symptoms of patients with mild to moderate DLB, and might be an option for treatment of these patients.
FUNDING: Lundbeck.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 20729148  Lancet Neurol. 2010 Oct;9(10):969-77. doi: 10.1016/S147・・・
著者: C Johansson, C Ballard, O Hansson, S Palmqvist, L Minthon, D Aarsland, E Londos
雑誌名: Int J Geriatr Psychiatry. 2011 Feb;26(2):206-13. doi: 10.1002/gps.2516.
Abstract/Text OBJECTIVE: This 30-week extension trial was a continuation of the first double-blind randomized controlled trial (RCT) to study memantine in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The objective was to evaluate the presence of recurrence of symptoms upon drug withdrawal. Furthermore, the aim was to explore washout dynamics in order to inform clinical practice.
METHODS: Patients were enrolled from psychiatric, memory and neurological outpatient clinics in Norway, Sweden and the UK. The trial comprised a 4-week washout period and a 26-week open-label treatment period. Outcome measures were presence of recurrence of symptom upon drug withdrawal, Clinical Global Impression of Change (CGIC) and modified motor Unified Parkinson's Disease Rating Scale (UPDRS).
RESULTS: recurrence of symptoms occurred more frequently (p=0.04) in patients receiving memantine (58%) than in patients receiving placebo (25%). There was a significant global deterioration (p=0.0003) during washout within the memantine group as measured by CGIC. The patients seemed to recover during the open-label treatment, however these findings were non-significant.
CONCLUSIONS: The findings inform clinical practice that any possible memantine-associated benefits might be rapidly lost after drug withdrawal. The magnitude of deterioration suggests a symptomatic rather than a disease-modifying effect of the drug. Open-label results should merely be considered inspiration for future trials.

Copyright © 2010 John Wiley & Sons, Ltd.
PMID 20665553  Int J Geriatr Psychiatry. 2011 Feb;26(2):206-13. doi: 1・・・
著者: Dag Aarsland, Clive Ballard, Zuzana Walker, Fredrik Bostrom, Guido Alves, Katja Kossakowski, Iracema Leroi, Francisco Pozo-Rodriguez, Lennart Minthon, Elisabet Londos
雑誌名: Lancet Neurol. 2009 Jul;8(7):613-8. doi: 10.1016/S1474-4422(09)70146-2. Epub 2009 Jun 10.
Abstract/Text BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB.
METHODS: We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516.
FINDINGS: 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0.7, 95% CI 0.04-1.39; p=0.03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12.4, 95% CI 6.0-30.9; p=0.004), there were no significant differences between the groups in secondary outcome measures.
INTERPRETATION: Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings.
FUNDING: The Western Norway Regional Health Authority; H Lundbeck A/S.

PMID 19520613  Lancet Neurol. 2009 Jul;8(7):613-8. doi: 10.1016/S1474-・・・
著者: Roger Kurlan, Jeffrey Cummings, Rema Raman, Leon Thal, Alzheimer's Disease Cooperative Study Group
雑誌名: Neurology. 2007 Apr 24;68(17):1356-63. doi: 10.1212/01.wnl.0000260060.60870.89.
Abstract/Text OBJECTIVE: To assess the efficacy and tolerability of quetiapine for agitation or psychosis in patients with dementia and parkinsonism.
METHODS: Multicenter randomized, double-blind, placebo-controlled parallel groups clinical trial involving 40 patients with dementia with Lewy bodies (n = 23), Parkinson disease (PD) with dementia (n = 9), or Alzheimer disease with parkinsonian features (n = 8). The main outcome measure for efficacy was change in the Brief Psychiatric Rating Scale (BPRS) from baseline to 10 weeks of therapy. For tolerability it was change in the Unified PD Rating Scale (UPDRS) motor section over the same time period. The trial was confounded by the need for a design change and incomplete recruitment.
RESULTS: No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning.
CONCLUSIONS: Quetiapine was well-tolerated and did not worsen parkinsonism. Although conclusions about efficacy may be limited, the drug in the dosages used did not show demonstrable benefit for treating agitation or psychosis in patients with dementia and parkinsonism. These findings are in keeping with prior studies reporting limited efficacy of various medications for reducing behavioral problems in demented patients.

PMID 17452579  Neurology. 2007 Apr 24;68(17):1356-63. doi: 10.1212/01.・・・
著者: Hitoshi Takahashi, Keizo Yoshida, Takio Sugita, Hisashi Higuchi, Tetsuo Shimizu
雑誌名: Prog Neuropsychopharmacol Biol Psychiatry. 2003 May;27(3):549-53. doi: 10.1016/S0278-5846(03)00040-X.
Abstract/Text The authors describe here the clinical outcomes of quetiapine treatment in nine patients with dementia with Lewy bodies (DLB) who manifested psychotic symptoms and aggressive behavior. Patients who had a score of 3 or higher on any of the three items of the Neuropsychiatric Inventory (NPI), agitation/aggression, hallucinations, and delusions, were given quetiapine 25-75 mg/day. Each patient's clinical status was assessed at baseline and after 4 and 8 weeks of treatment by using the NPI, Mini-Mental State Examination (MMSE), and Simpson-Angus Scale (S-A). Five of nine patients had a positive response with a decline of more than 50% in the sum of scores for three items of the NPI. The other three patients withdrew from quetiapine treatment due to somnolence or orthostatic hypotension. The remaining patient exhibited no clinically significant change in the NPI score. The S-A scale was not affected by quetiapine treatment in any patient. These findings suggest that quetiapine may be effective in treating psychotic symptoms and disruptive behavior in some patients with DLB. Further placebo-controlled, randomized, double-blind trials with this drug are needed to confirm this observation.

PMID 12691793  Prog Neuropsychopharmacol Biol Psychiatry. 2003 May;27(・・・
著者: Hubert H Fernandez, Chuang-Kuo Wu, Brian R Ott
雑誌名: Expert Opin Pharmacother. 2003 Nov;4(11):2027-37. doi: 10.1517/14656566.4.11.2027.
Abstract/Text The syndrome of dementia with Lewy bodies (DLB) is characterised by the clinical triad of fluctuating cognitive impairment, recurrent visual hallucinations and spontaneous motor features of Parkinsonism. In an attempt to define DLB as a distinct clinical syndrome separate from Alzheimer's disease (AD) and Parkinson's disease (PD) with dementia, a consensus workshop in 1995 established a new set of diagnostic criteria. Dementia that precedes or accompanies the onset of spontaneous (i.e., not neuroleptic-induced) Parkinsonism is termed DLB. In addition, fluctuations in alertness, cognition and function and visual hallucinations are emphasised and included as core features of DLB. The degree to which an individual patient exhibits cognitive impairment, behavioural problems and Parkinsonian features is variable. Therefore, treatment must be individualised. Although there are no officially approved drugs for DLB, limited experience from clinical trials, as well as past experience with the treatment of AD and PD patients, provide some basis for making drug choices. The cholinergic deficit seen in DLB makes cholinesterase inhibitor drugs the mainstay of treatment for cognitive impairment. This class of drugs has also shown therapeutic benefit in reducing hallucinations and other neuropsychiatric symptoms of the disease. Because of their relatively greater therapeutic window, cholinesterase inhibitors are also used as first-line therapy for the treatment of psychosis in DLB. Patients with DLB are extremely sensitive to the extrapyramidal side effects of neuroleptic medications. Thus, only atypical antipsychotic agents such as quetiapine, should be considered as alternative treatment for psychosis. Anxiety and depression are best treated with selective serotonin re-uptake inhibitors, whereas REM sleep behaviour disorder may be treated with low dose clonazepam. Parkinsonism responds to dopaminergic agents; however, precipitation or aggravation of hallucinosis may occur. Levodopa is preferred over dopamine agonists due to its lower propensity to cause hallucinations and somnolence. As the diagnostic criteria for DLB become more refined and validated by postmortem studies, it is hoped that rigorous, well-designed trials will be performed, aimed at alleviating the primary target symptoms of dementia, psychosis and Parkinsonism.

PMID 14596656  Expert Opin Pharmacother. 2003 Nov;4(11):2027-37. doi: ・・・
著者: Hubert H Fernandez, Martha E Trieschmann, Monica A Burke, Joseph H Friedman
雑誌名: J Clin Psychiatry. 2002 Jun;63(6):513-5.
Abstract/Text BACKGROUND: Most clinicians perceive psychosis in dementia with Lewy bodies (DLB) as more difficult to treat than Parkinson's disease, yet there are no reports comparing the antipsychotic response between the 2 disorders.
METHOD: All charts of Parkinson's disease and DLB patients at our Movement Disorders Center, Memorial Hospital of Rhode Island, Pawtucket, given quetiapine for psychosis were reviewed. Demographic data, including type and severity of psychosis, before and after Unified Parkinson's Disease Rating Scale (UPDRS)-motor scores, motor worsening, and treatment response (recorded as poor/none, partial, or total), were obtained. The chi-square test was used to assess differences in efficacy and tolerability of quetiapine between Parkinson's disease and DLB patients.
RESULTS: Eighty-seven Parkinson's disease and 11 DLB patients with psychosis were analyzed. No significant difference in mean age, levodopa dose, quetiapine dose, duration of quetiapine use, or baseline UPDRS-motor score was noted between Parkinson's disease and DLB patients. Eighty percent (70/87) of Parkinson's disease patients and 90% (10/11) of DLB patients had partial to complete resolution of psychosis using quetiapine (p = .40). Motor worsening was noted at one point in 32% (28/87) of Parkinson's disease and 27% (3/11) of DLB patients over the duration of quetiapine use (p = .74).
CONCLUSION: Long-term quetiapine use was generally well tolerated in this geriatric Parkinson's disease and DLB population. Mild motor worsening occurred in some patients. No significant difference in long-term efficacy and motor worsening associated with quetiapine treatment was noted between the 2 disorders.

PMID 12088163  J Clin Psychiatry. 2002 Jun;63(6):513-5.
著者: Jeffrey L Cummings, Jamie Street, Donna Masterman, W Scott Clark
雑誌名: Dement Geriatr Cogn Disord. 2002;13(2):67-73. doi: 48636.
Abstract/Text OBJECTIVE: This study sought to determine whether patients with dementia with Lewy bodies (DLB) and psychosis responded to treatment with olanzapine.
METHODS: This was a post hoc analysis of a subgroup of patients with DLB included in a larger double-blind, placebo-controlled, randomized parallel group trial of olanzapine for the treatment of psychosis in patients with Alzheimer's disease. Patients meeting the consensus criteria for DLB and exhibiting parkinsonism and visual hallucinations were selected from the initial study. Psychosis was assessed with the Neuropsychiatric Inventory/Nursing Home (NPI-NH) version and the Brief Psychiatric Rating Scale (BPRS). Extrapyramidal symptoms were evaluated with the Simpson-Angus scale.
RESULTS: Twenty-nine patients met the criteria for DLB; 10 were randomized to placebo, 5 received 5 mg of olanzapine, 7 received 10 mg of olanzapine and 7 received 15 mg of olanzapine. Patients with DLB treated with 5 mg of olanzapine showed significant reductions in delusions and hallucinations. Patients treated with 10 mg showed a significant reduction in the NPI-NH delusion subscale score. No significant differences were found between the 15-mg group and the placebo group. Confirmatory findings emerged from an analysis of the BPRS. Caregivers reported decreased disruptions in their occupational routines for the group receiving 5 or 10 mg of olanzapine. There was no significant exacerbation of parkinsonian symptoms in any study group, no decrement in Mini-Mental State Examination scores in any of the treatment groups, and symptoms suggestive of anticholinergic toxicity did not differ among treatment groups.
CONCLUSIONS: This preliminary analysis suggests that olanzapine (5 or 10 mg) reduces psychosis in patients with DLB without worsening parkinsonism.

Copyright 2002 S. Karger AG, Basel
PMID 11844887  Dement Geriatr Cogn Disord. 2002;13(2):67-73. doi: 4863・・・
著者: R L Allen, Z Walker, P J D'Ath, C L Katona
雑誌名: Lancet. 1995 Jul 15;346(8968):185.
Abstract/Text
PMID 7541499  Lancet. 1995 Jul 15;346(8968):185.
著者: I G McKeith, C G Ballard, R W Harrison
雑誌名: Lancet. 1995 Sep 9;346(8976):699.
Abstract/Text
PMID 7544860  Lancet. 1995 Sep 9;346(8976):699.
著者: Masayuki Morikawa, Toshifumi Kishimoto
雑誌名: Can J Psychiatry. 2002 Dec;47(10):976.
Abstract/Text
PMID 12553140  Can J Psychiatry. 2002 Dec;47(10):976.
著者: Hideto Shinno, Etsuko Utani, Shihoh Okazaki, Tetsuya Kawamukai, Hideaki Yasuda, Takuji Inagaki, Yasushi Inami, Jun Horiguchi
雑誌名: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Oct 1;31(7):1543-5. doi: 10.1016/j.pnpbp.2007.07.002. Epub 2007 Aug 3.
Abstract/Text
PMID 17688986  Prog Neuropsychopharmacol Biol Psychiatry. 2007 Oct 1;3・・・
著者: Koh Iwasaki, Masahiro Maruyama, Naoki Tomita, Katsutoshi Furukawa, Miyako Nemoto, Hironori Fujiwara, Takashi Seki, Masahiko Fujii, Manabu Kodama, Hiroyuki Arai
雑誌名: J Clin Psychiatry. 2005 Dec;66(12):1612-3.
Abstract/Text
PMID 16401166  J Clin Psychiatry. 2005 Dec;66(12):1612-3.
著者: Koh Iwasaki, Kenji Kosaka, Hideo Mori, Reina Okitsu, Katsutoshi Furukawa, Yuta Manabe, Mitsuhiro Yoshita, Aya Kanamori, Nobuo Ito, Kenji Wada, Michio Kitayama, Jun Horiguchi, Shuhei Yamaguchi, Shin Takayama, Ryuji Fukuhara, Shinji Ouma, Seigo Nakano, Mamoru Hashimoto, Toru Kinoshita
雑誌名: Psychogeriatrics. 2012 Dec;12(4):235-41. doi: 10.1111/j.1479-8301.2012.00413.x.
Abstract/Text BACKGROUND: This multicentre open-label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies.
METHODS: Sixty-three dementia with Lewy bodies patients with probable BPSD (M:W, 30:33; mean age, 78.2±5.8 years) were enrolled and treated with YKS for 4 weeks.
RESULTS: Significant improvements in Neuropsychiatric Inventory scores (mean decrease, 12.5 points; P<0.001) and Zarit Burden Interview-Japanese edition tests (mean decrease, 3.6 points; P=0.024) were observed. In patients who consented to an assessment after 2 weeks of treatment, a time-dependent significant improvement was observed in the Neuropsychiatric Inventory score (n=23; mean decrease, 14.4; P<0.001), each subscale, including delusions and hallucinations, the Zarit Burden Interview-Japanese edition (n=22; mean decrease, 8.2; P<0.01) and the behavioural pathology in Alzheimer's disease insomnia subscale. The Mini-Mental State Examination and the Disability Assessment for Dementia (DAD) showed no significant change. Adverse events were observed in 11 (18%) patients. Three patients (5%) discontinued YKS due to adverse reactions, namely, spasticity and exacerbation of BPSD, edema, and nausea. Hypokalaemia (<3.5 mEq/L) was present in four patients (6%) at the study endpoint. Worsening of extrapyramidal symptoms was not observed.
CONCLUSION: YKS improved BPSD in dementia with Lewy bodies patients and caregiver burden scores without deterioration in cognitive function. YKS is useful for the treatment of delusions and hallucinations in BPSD.

© 2012 The Authors. Psychogeriatrics © 2012 Japanese Psychogeriatric Society.
PMID 23279145  Psychogeriatrics. 2012 Dec;12(4):235-41. doi: 10.1111/j・・・
著者: J B Grace, M P Walker, I G McKeith
雑誌名: Int J Geriatr Psychiatry. 2000 Nov;15(11):1028-33.
Abstract/Text INTRODUCTION: Sleep disturbances are common in healthy old age and in dementia syndromes. Polysomnography has demonstrated typical changes in both Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) with AD being characterised by sundowning and sleep apnoea and DLB patients showing more disturbances of movement control during sleep. The technical difficulties associated with EEG sleep recordings mean that polysomnography is not possible out of specialist centres.
OBJECTIVES: To use questionnaires to assess the frequency of sleep disturbances in patients with Alzheimer's disease and dementia with Lewy bodies.
METHOD: The sleep profiles of twenty patients with AD and 17 with DLB were assessed using three questionnaires, one designed to assess night time sleep disturbance, one day time sleepiness and the last carer burden. The sleep questionnaires were repeated in a subgroup after treatment with a cholinesterase inhibitor (rivastigmine).
RESULTS: Level of sleep disturbance in both groups was high. DLB patients had more overall sleep disturbance, more movement disorders whilst asleep and more abnormal day time sleepiness. Treatment with rivastigmine produced a trend towards normalisation of sleep profile in a small number of subjects.
CONCLUSIONS: Both groups have extensive sleep problems. The DLB and AD groups have different sleep profiles that are of diagnostic importance and may suggest different treatment strategies. The results are consistent with those found from polysomnographic assessment and suggest that the questionnaires used are sensitive to detect differences previously documented with polysomnography.

PMID 11113983  Int J Geriatr Psychiatry. 2000 Nov;15(11):1028-33.
著者: E J Olson, B F Boeve, M H Silber
雑誌名: Brain. 2000 Feb;123 ( Pt 2):331-9.
Abstract/Text We describe demographic, clinical, laboratory and aetiological findings in 93 consecutive patients with rapid eye movement (REM) sleep behaviour disorder (RBD), which consists of excessive motor activity during dreaming in association with loss of skeletal muscle atonia of REM sleep. The patients were seen at the Mayo Sleep Disorders Center between January 1, 1991 and July 31, 1995. Eighty-one patients (87%) were male. The mean age of RBD onset was 60.9 years (range 36-84 years) and the mean age at presentation was 64.4 years (37-85 years). Thirty-two per cent of patients had injured themselves and 64% had assaulted their spouses. Subdural haematomas occurred in two patients. Dream content was altered and involved defence of the sleeper against attack in 87%. The frequency of nocturnal events decreased with time in seven untreated patients with neurodegenerative disease. MRI or CT head scans were performed in 56% of patients. Although four scans showed brainstem pathology, all of these patients had apparently unrelated neurodegenerative diseases known to be associated with RBD. Neurological disorders were present in 57% of patients; Parkinson's disease, dementia without parkinsonism and multiple system atrophy accounted for all but 14% of these. RBD developed before parkinsonism in 52% of the patients with Parkinson's disease. Five of the 14 patients with multiple system atrophy were female, and thus the strong male predominance in RBD is less evident in this condition. Psychiatric disorders, drug use or drug withdrawal were rarely causally related to RBD. Clonazepam treatment of RBD was completely or partially successful in 87% of the patients who used the drug. We conclude that RBD is a well-defined condition and that descriptions from different centres are fairly consistent. It is commonest in elderly males and may result in serious morbidity to patients and bed partners. There is a strong relationship to neurodegenerative disease, especially Parkinson's disease, multiple system atrophy and dementia, and neurologists should explore the possibility of RBD in patients with these conditions. RBD symptoms may be the first manifestations of these disorders and careful follow-up is needed. Neuroimaging is unlikely to reveal underlying disorders not suspected clinically. We confirm the effectiveness of clonazepam, but note that attention to the safety of the bed environment may be sufficient for patients with contraindications to the drug.

PMID 10648440  Brain. 2000 Feb;123 ( Pt 2):331-9.
著者: Gloria Massironi, Samantha Galluzzi, Giovanni B Frisoni
雑誌名: Int Psychogeriatr. 2003 Dec;15(4):377-83.
Abstract/Text BACKGROUND: Dementia with Lewy bodies (DLB) is often associated with REM sleep behavior disorders (RBD) characterized, in contrast to the usual paralysis of REM sleep, by violent motor and verbal activity.
PATIENTS AND METHODS: The pharmacological management of RBD was investigated in three DLB patients treated with clonazepam, a benzodiazepine used as an antiepileptic, or donepezil, a cholinesterase inhibitor.
RESULTS: All three patients had marked improvement. The pharmacodynamic mechanisms underlying the efficacy of the two drugs might be due to facilitator effect on the pedunculopontine nucleus, a key structure in the physiology of REM sleep.

PMID 15000417  Int Psychogeriatr. 2003 Dec;15(4):377-83.
著者: Soichi Mizuno, Atsuko Kameda, Takuji Inagaki, Jun Horiguchi
雑誌名: Psychiatry Clin Neurosci. 2004 Dec;58(6):660-5. doi: 10.1111/j.1440-1819.2004.01317.x.
Abstract/Text The aim of this study was to observe the effects of donepezil on both the cognitive function and sleep patterns in patients of Alzheimer's Type Dementia (ATD), especially to determine the relationship between the improvement of cognitive function and the amount of rapid eye movement (REM) sleep. A total of 12 patients (7 females, 5 males; age, 73.0 +/- 6.8) meeting the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) criteria of probable AD were studied. These patients presented with mild to moderate dementia, which was confirmed by a Clinical Dementia Rating score of 1 or 2. Following baseline examinations consisting of the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and polysomnography (PSG), 5 mg of donepezil was administered to the patients at breakfast every day. All patients were reassessed 6 weeks later using the same examinations. With sleep patterns, the percentage of REM sleep to total sleep time increased after the administration of donepezil. In addition, it was also found that sleep efficiency was increased and sleep latency was shortened by this administration. Although the ADAS-Jcog score did not decrease significantly, there was significant positive correlation between the decrease of the ADAS-Jcog score and the increase in the percentage of REM sleep. These results indicate the increase action of REM sleep due to activate central cholinergic systems and the possibility to improve sleep conditions due to one-time administration after breakfast of donepezil in mild to moderate ATD. It is concluded that the increase in REM sleep may reflect the improvement of cognitive function in ATD patients.

PMID 15601392  Psychiatry Clin Neurosci. 2004 Dec;58(6):660-5. doi: 10・・・
著者: Hideto Shinno, Yasushi Inami, Takuji Inagaki, Yu Nakamura, Jun Horiguchi
雑誌名: Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr 1;32(3):881-5. doi: 10.1016/j.pnpbp.2007.12.027. Epub 2008 Jan 11.
Abstract/Text OBJECTIVE: Recently, traditional herbal medicines have been reported to be effective for behavioral and psychological symptoms of dementia (BPSD). This study aims to examine the efficacy of Yi-Gan San (YGS) in the improvement of BPSD and sleep disorders in patients with dementia.
METHODS: Five patients (1 male and 4 female) with dementia in accordance with DSM-IV criteria were investigated. Participants were treated with YGS for 4 weeks. The Nursing Home version of Neuropsychiatric Inventory (NPI-NH) for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, polysomnography for evaluation of sleep structure, and the Pittsburgh Sleep Quality Index for subjective sleep quality were carried out at baseline and at the end of treatment.
RESULTS: All patients completed the trial. Significant improvements in the total NPI-NH score (34.0+/-6.5 to 12.8+/-6.6) as well as delusions, hallucinations, agitation/aggression, anxiety, and irritability/lability, whereas MMSE scores were unchanged. PSG revealed increases in total sleep time, sleep efficiency, stage 2 sleep, and decreases in the number of arousals and periodic limb movements. Subjective sleep quality was also improved. No adverse effects were observed.
CONCLUSION: YGS was effective for BPSD and sleep disturbances, and well tolerated in patients with dementia. Further examinations using a double-blind placebo-controlled design are necessary.

PMID 18243460  Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr 1;3・・・
著者: Bradley F Boeve, Michael H Silber, Tanis J Ferman
雑誌名: Sleep Med. 2003 Jul;4(4):281-4.
Abstract/Text OBJECTIVE: To describe the treatment response with melatonin for rapid eye movement (REM) sleep behavior disorder (RBD) associated with other neurologic disorders.
BACKGROUND: Clonazepam has been considered the treatment of choice for RBD. However, an alternative treatment is desirable for those with RBD refractory to clonazepam, for those who experience intolerable side-effects with clonazepam, and for those in whom clonazepam precipitates or aggravates obstructive sleep apnea (OSA). To date, there is minimal published data and limited follow-up regarding the use of melatonin for patients with RBD associated with other neurologic syndromes and disorders.
DESIGN/METHODS: The response to melatonin treatment for RBD was reviewed on consecutive patients the investigators treated with this agent at Mayo Clinic Rochester from January 2000 to June 2001. The coexisting neurologic disorders, reasons for using melatonin, effective doses, side-effects, and duration of follow-up were also reviewed on all patients.
RESULTS: Fourteen patients were commenced on melatonin over the specified time period (13 male, median RBD onset age 56 years, range 20-77 years). The coexisting neurologic findings/disorders were dementia with Lewy bodies (n=7), mild cognitive impairment with mild parkinsonism (n=2), multiple system atrophy (n=2), narcolepsy (n=2), and Parkinson's disease (n=1). The reasons for using melatonin in these cases were incomplete response of RBD to clonazepam in six patients, existing cognitive impairment in five, intolerable side-effects with clonazepam in two, and presence of severe obstructive sleep apnea and narcolepsy in one. With seven patients continuing to use clonazepam at 0.5-1.0 mg/night, RBD was controlled in six patients, significantly improved in four, and initially improved but subsequently returned in two; no improvement occurred in one patient and increased RBD frequency/severity occurred in one patient. The effective melatonin doses were 3 mg in two cases, 6 mg in seven cases, 9 mg in one case, and 12 mg in two cases. Five patients reported side-effects, which included morning headaches (2), morning sleepiness (2), and delusions/hallucinations (1); these symptoms resolved with decreased dosage. The mean duration of follow-up was 14 months (range 9-25 months), with eight patients experiencing continued benefit with melatonin beyond 12 months of therapy.
CONCLUSIONS: In this series, persistent benefit with melatonin beyond 1 year of therapy occurred in most but not all patients. Melatonin can be considered as a possible sole or add-on therapy in select patients with RBD. Prospective, long-term, controlled trials with melatonin are warranted in a larger number of patients with RBD associated with a variety of neurologic symptoms and disorders.

PMID 14592300  Sleep Med. 2003 Jul;4(4):281-4.
著者: N Takeuchi, N Uchimura, Y Hashizume, M Mukai, Y Etoh, K Yamamoto, T Kotorii, H Ohshima, M Ohshima, H Maeda
雑誌名: Psychiatry Clin Neurosci. 2001 Jun;55(3):267-9. doi: 10.1046/j.1440-1819.2001.00854.x.
Abstract/Text Rapid eye movement sleep behavior disorder (RBD) is a parasomnia with clinical symptoms that include punching, kicking, yelling and leaping out of bed in sleep. Polysomnographic (PSG) finding showed REM sleep without muscle atonia. Clonazepam is generally used for treating RBD symptoms but melatonin was reported to be effective so we reconfirmed the effect of melatonin on RBD patients in the present study. We used melatonin (3-9 mg/day) which could ameliorate problem sleep behaviors remarkably, as well as %tonic activity in PSG variables. In the present study, melatonin was reconfirmed to be effective in RBD symptoms, especially for patients with low melatonin secretion, while its mechanism was not clearly known in the present study.

PMID 11422870  Psychiatry Clin Neurosci. 2001 Jun;55(3):267-9. doi: 10・・・
著者: I McKeith, A Fairbairn, R Perry, P Thompson, E Perry
雑誌名: BMJ. 1992 Sep 19;305(6855):673-8.
Abstract/Text OBJECTIVE: To determine the outcome of administration of neuroleptics to patients with senile dementia of Lewy body type confirmed at necropsy.
DESIGN: Retrospective analysis of clinical notes blind to neuropathological diagnosis.
SETTING: Specialist psychogeriatric assessment units referring cases for necropsy to a teaching hospital neuropathology service.
PATIENTS: 41 elderly patients with diagnosis of either Alzheimer type dementia (n = 21) or Lewy body type dementia (n = 20) confirmed at necropsy.
MAIN OUTCOME MEASURES: Clinical state including extrapyramidal features before and after neuroleptic treatment and survival analysis of patients showing severe neuroleptic sensitivity compared with the remainder in the group.
RESULTS: 16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2.70 (95% confidence interval 2.50-8.99); (chi 2 = 2.68, p = 0.05). By contrast, only one (7%) of 14 patients with Alzheimer type dementia given neuroleptics showed severe neuroleptic sensitivity.
CONCLUSIONS: Severe, and often fatal, neuroleptic sensitivity may occur in elderly patients with confusion, dementia, or behavioural disturbance. Its occurrence may indicate senile dementia of Lewy body type and this feature has been included in clinical diagnostic criteria for this type of dementia.

PMID 1356550  BMJ. 1992 Sep 19;305(6855):673-8.
著者: Margaret M Swanberg, Jeffrey L Cummings
雑誌名: Drug Saf. 2002;25(7):511-23.
Abstract/Text Dementia with Lewy bodies (DLB) is a relatively recently characterised syndrome with clinical and pathological features that distinguish it from classical Alzheimer's disease. These characteristics include more rapid decline, spontaneous features of parkinsonism, visual hallucinations and fluctuating cognition. This article reviews the clinical syndrome of DLB and the agents used to treat its cognitive, motor and behavioural manifestations. Benefit-risk issues regarding the treatment of DLB are discussed based upon limited randomised, controlled clinical trials with some speculative conclusions being drawn from case reports and case series. We conclude that patients with DLB may respond better to cholinesterase inhibitors than patients with Alzheimer's disease on both cognitive and behavioural measures. Cholinesterase inhibitor therapy may result in reduced caregiver burden and less time institutionalised. These agents are well tolerated with the majority of adverse effects being gastrointestinal in nature. Although neuropsychiatric manifestations are numerous in patients with DLB, antipsychotics should be used infrequently and with caution, although atypical antipsychotics are better tolerated than conventional antipsychotics. Physicians should exhibit caution when prescribing these agents because of the increased risk of extrapyramidal adverse effects. Limited data suggest that the use of levodopa or other dopaminergic agents may be of benefit for the treatment of the parkinsonism that is associated with DLB. However, the increased risk of hallucinations and neuropsychiatric symptoms may negate the potential benefits of increased mobility. There is insufficient evidence to draw conclusions about the use of antidepressants; however, selective serotonin reuptake inhibitors may be of benefit.

PMID 12093309  Drug Saf. 2002;25(7):511-23.

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