Beyond TDP-432009/03/28 13:23:35

NatureとCellに重要な解説記事がのってます。


Kristel Sleegers & Christine Van Broeckhoven
Nature 458, 415-417 (26 March 2009) | doi:10.1038/458415a; Published online 25 March 2009
Motor-neuron disease: Rogue gene in the family

Clotilde Lagier-Tourenne andDon W. Cleveland
Cell, Volume 136, Issue 6, 1001-1004, 20 March 2009
Rethinking ALS: The FUS about TDP-43

いずれも2月にScienceにでたALSの新たな原因遺伝子の発見をふまえてのものです。第16染色体のsarcoma/translated in liposarcoma(FUS/TLS) geneというきいたことない遺伝子ですが、この遺伝子は、TDP-43と同じくDNA/RNA binding proteinで核蛋白代謝というまったく基本的知識のない機能に関係する物質である。これから類推すると、ALSの病因には、核RNA代謝の異常が考えられ、他の既知の遺伝子たとえばELP3など検索の必要があるとのこと。ここからまた無数の研究がでてきそうだ。傍観者としても眼がはなせません。

臨床では、核蛋白代謝なんて無縁であったが、RNAに関する基本を学習する必要がでてきた。

Primary CNS lymphoma2007/01/15 07:29:41

Nature Clinical Practice Neurology 3:24-35,2007
Hochberg FH et al.
Primary CNS lympphoma

最新の頭のlymphomaのreview. 去年ほとんどreviewしている(山形済生館医誌31:20-26,2006)ので、追加事項をcheckする。
本論文ではMLの腫瘍細胞発生機序について考察している。EB virus説について解説している。MLのMR画像を示すFigure1は必見。MRSの所見をみせている。high dose MTXとradiationで3年のprogression-free survicalと5年生存。high dose MTXでも3年で再発。再発しても50%はまた寛解へ(そんなもんだ)現在おこなわれているclinical trialはMTXと何かの組み合わせばかり。neurolymphomatosisについても引用。lymphomatosis cerebriは記載なし。

Clinical Neuroscienceの2007年1月号で、<画像で見る神経疾患>のところで、愛媛大学の方がlymphomatosis cerbriの写真を掲載。自験例の方が圧倒的にdemonstrable!

Vascular cognitive impairment2006/10/13 17:11:00

Nature Clinical Practice Neurology (2006) 2, 538-547

Vascular cognitive impairment

Ola A Selnes* and Harry V Vinters

Cognitive impairment commonly accompanies clinical syndromes associated with vascular disease of the brain. Because of evolving definitional criteria, however, the frequency of cognitive impairment attributable to cerebrovascular disease is difficult to determine. Dementia occurs in up to one-third of elderly patients with stroke, a subset of whom have Alzheimer's disease (AD) rather than a pure vascular dementia syndrome. In fact, pure vascular dementia has been shown to be uncommon in most large autopsy series. A mixed etiology of AD and cerebrovascular disease is thought to become more common with increasing age, although no clinical criteria for the diagnosis of AD with cerebrovascular disease are currently available. Epidemiological studies have implicated subcortical small-vessel disease as a risk factor for cognitive impairment and dementia, but the cognitive expression and clinical significance of MRI white matter changes in individual patients is difficult to establish. The frequency of specific neuropathologic features of vascular cognitive impairment depends largely on study inclusion criteria. Cerebral meningocortical microangiopathies with distinctive clinicopathological profiles are associated with dementia in both sporadic cases and familial syndromes. In patients with AD, the contribution of amyloid-beta protein to the degree of cognitive impairment has not been clearly defined.

  1. フレアでだれにでもみられる白質の白い病変をsubcortical small-vessel ischemic diseaseとよぶ。 これには高血圧、糖尿病、遺伝因子と年齢が関与する。 そしてこの病変が将来の痴呆の危険因子となる。 Alzheimer病の脳血管病変は最近注目されている。 遺伝性のある疾患としてCADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathyがある。 NOTCH3 geneの異常である。
  2. 脳梗塞の病理分類 cystic infarction(1cm以上) lacunar infarction(1cm以下、肉眼的に確認) == Ia,Ib,II--an old microhemorrhage with abundant hemosiderin-laden macrophages microinfarct(肉眼でわからず)
  3. 海馬の硬化--現在ではvascular dementiaの老人に共通に認められる所見
  4. Amyloid angiopathy vascular dementiaおよびAlzheimerに関与

CNS control of food intake and body weight2006/10/01 07:30:21

Nature 443, 289-295(21 September 2006) 医学:中枢神経系による摂食量と体重の制御 . (Title in English; Central nervous system control of food intake and body weight).

G. J. Morton1, D. E. Cummings2, D. G. Baskin2,3, G. S. Barsh4 and M. W. Schwartz1

エネルギー必要量の変化に応じて摂食量を調節する能力は、生存のために必須である。最近の研究の進展から、体脂肪貯蔵量の変化を摂食行動の適応調整へと結びつける分子レベル、細胞レベルおよび行動レベルの作用機序についての手がかりが得られている。この恒常性調節機構の生理的な重要性は、そこの主要ないくつかの要素のどれが機能障害に陥っても重度肥満が生じることで明らかである。こうした新たな情報から、世界的な肥満の蔓延について考察するための枠組みとなる生物学的背景が得られ、治療的介入や将来の研究に向けてとりうる多くの道筋が見えてくる。

Aβ star: a light onto synaptic dysfunction?2006/07/24 07:20:30

Nature Medicine 12, 760 - 761 (2006) doi:10.1038/nm0706-760

Learning and memory is impaired in a mouse model of Alzheimer disease. An Aβ12-mer called Aβ* may be responsible for these cognitive deficits.

The ups and downs of Abeta2006/07/23 08:00:16

Nature Medicine 12, 758 - 759 (2006) doi:10.1038/nm0706-758 Dennis J Selkoe

How do A levels increase in individuals with Alzheimer disease? Recent work suggests that some forms of neuronal activity can drive Abeta accumulation in the brain.

Neuronal release of the peptide is physiologically regulated by synaptic activity throughout life.(Cirrito, J.R. et al. Neuron 48, 913–922 (2005))

Physiological (and pharmacological) changes in neuronal activity, especially synaptic activity, may continuously alter the levels of both A40 and the far more amyloidogenic A42 species in brain regions prone to formation of amyloid plaques.

Aβの生理的役割にするneuronの図がでています。

Amyloid at the blood vessel wall2006/07/20 07:34:40

Nature Medicine 12, 756 - 757 (2006) doi:10.1038/nm0706-756

An APP gene duplication found in French families with beta-amyloidopathy suggests a link between dementia and the vasculature.

AlzheimerとAmyloid angiopathy(AA)はきってもきれない関係にあり、昔Alzheimerの100%がAAだと書いてあったが、最近学習した時には70%になっていた。遺伝性のAAがあることがよく知られている。

Nature Genetics 38, 24 - 26 (2006) Published online: 20 December 2005; | doi:10.1038/ng1718

APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy Anne Rovelet-Lecrux et al.

We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA). Among these families, the duplicated segments had a minimal size ranging from 0.58 to 6.37 Mb. Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides. Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.

このAPP duplicationsの人の表現型はさまざまで、痴呆、出血、その両者の場合がある。APPの変異で発生する(Flemish mutation)と似ている。あるいはDutch Type AAとも。

Genetic variability in the expression of these loci contribute to the risk of 'sporadic' disease.つまり我々のよく知るAAにもこういったのが関与する。Singleton, A. , Myers, A. & Hardy, J. Hum. Mol. Genet. 13, R123–R126 (2004) Down(trisomy 21)の人は脳出血しない。 amylopidopathy における血管と実質病変のoverlapについては再考を要する。 Abeta vaccination(AN1792)のmeningoencephalitisには抗体によるmicrovascular damageが関与。

Alzheimerもmicrohemorrhageで、症状の進展にもvascular lesionが関与しているものと考えられる。

APP is involved in blood clotting.(PNAS 102.18135-18140,2005 Abetaにはdamage-response roleがある。出血したときの血管のvascular sealant。neuronal depressant。生理作用もあるらしい。

Can the immune system fight Alzheimer disease?2006/07/18 21:18:19

Nature Medicine 12, 755 - 756 (2006) doi:10.1038/nm0706-755

Mobilizing the immune system may be a promising strategy to fight Alzheimer disease. A clinical trial has shed light on the therapeutic potential—and the pitfalls—of Aß immunization.

Schenk, D. et al. Nature 400, 173–177 (1999) the startling discovery that immunizing transgenic mice that overexpressed human amyloid with the human Abeta42 peptide(AN-1792) prevented the expected buildup of amyloid plaques in the brain

Clinical trial Gilman, S. et al. Neurology 64, 1553–1562 (2005) Fox, N.C. et al. Neurology 64, 1563–1572 (2005)

An unexpected serious adverse event when 6% of the treated individuals developed meningoencephalitis

Pinpointing plaques with PIB2006/07/17 17:50:28

Nature Medicine 12, 753 - 754 (2006) doi:10.1038/nm0706-753

The promise of disease-modifying treatments for Alzheimer disease calls for biomarkers that enable early diagnosis. A new discovery shows how to visualize amyloid pathology in living Alzheimer patients.

In a recent paper(Klunk, W.E. et al. Ann. Neurol. 55, 306–319 (2004). ), Klunk and coworkers introduced amyloid imaging as a new principle, enabling direct visualization of amyloid plaques in the living human brain. Using a novel positron emission tomography (PET) tracer called Pittsburgh Compound-B (PIB), the authors found marked retention of the molecule in Alzheimer disease patients in areas of the brain known to contain large amounts of A plaques.

Alzheimer disease2006/07/17 16:06:31

Nature Medicine 2006年6月 Focus の特集。onlineでfreeでみれます。しばらくこれを抄読します。

Introduction

From imaging to immunotherapy, and synapses to -secretase: these are among the most exciting findings in the field of Alzheimer disease from the past three years, according to leading scientists. Many hope that these discoveries will soon lead to a cure for this devastating illness, which affects approximately 4.5 million individuals in the US alone. In countries such as Japan, where the proportion of aged individuals is expected to almost double over the next 50 years, tackling Alzheimer disease is crucial for safeguarding the health of the population...........

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