Multiple cerebral infarcts with a few vasculitic lesions in the chronic stage of cerebral amyloid angiopathy‐related inflammation

We report a 75‐year‐old man with a 3.5‐year history of cerebral amyloid angiopathy (CAA)‐related inflammation. His initial symptom was headache and sensory aphasia appeared 1 month later. Brain MRI revealed features compatible with meningoencephalitis involving the right frontal, parietal and temporooccipital lobes. A brain biopsy sample from the right parietal lobe showed thickening of the leptomeninges, and granulomatous vasculitis with multinucleated giant cells and vascular Aβ deposits. No vascular lesions were evident by cerebral angiography. Serological examination revealed an elevated level of proteinase 3 anti‐neutrophil cytoplasmic autoantibodies (PR3‐ANCA). The patient was treated with corticosteroids, but this was only partially and temporarily effective. Autopsy revealed marked leptomeningeal thickening with inflammatory cell infiltrates and hemosiderin deposits, many superficial predominantly small infarcts at various stages in the cerebral cortex and only a few cerebral active vasculitic lesions. Immunohistochemically, CAA showing widespread Aβ‐positive blood vessels with double‐barrel formations was demonstrated. In conclusion, we consider that, although the association of PR3‐ANCA with the pathogenesis of Aβ‐associated vasculitis remained unclear, the present case represents a rare example of CAA‐related inflammation at the chronic stage.     

Do amyloid structures formed by Staphylococcus aureus phenol-soluble modulins have a biological function?

Phenol-soluble modulins (PSMs) are alpha-helical, amphipathic peptides that have multiple functions in staphylococcal physiology and virulence. Recent research has suggested that PSMs form amyloid fibrils and amyloids are involved in PSM-mediated phenotypes such as cytolysis and biofilm stability. While we observed PSM amyloid formation using electron microscopy and dye assays, there were no apparent differences in the production of extracellular fibrous material between a PSM-deficient strain and the isogenic wild-type strain. Furthermore, we detected no correlation between cytolytic or pro-inflammatory activities with the propensity of PSM derivatives to form amyloids. In addition, we propose a model based on our finding of non-specific attachment of PSMs to DNA, which we here report results in resistance to DNase digestion, explaining previous findings on PSM-mediated biofilm stability without the necessity to assume amyloid involvement. Collectively, our results indicate that PSM amyloid formation may not be of major relevance for known key biological functions of PSMs. Intriguingly, however, we found that amyloid-forming capacity of PSMalpha3 allows almost no amino acid exchanges, suggesting importance of amyloid formation in possibly yet unknown functions of PSMs.     

When astrocytes become harmful: Functional and inflammatory responses that contribute to Alzheimer's disease

A growing body of research suggests that astrocytes play roles as contributors to the pathophysiology of Alzheimer's disease (AD). Several lines of evidence propose that activated astrocytes produce and release proinflammatory molecules that may be critical for the generation of amyloid-β peptide (Aβ). However, accumulating evidence indicates that Aβ may activate astrocytes, which leads to an increase in cytokines that has been suggested to be a causative factor in the cognitive dysfunction of AD; thus, a vicious circle may be created. Intrinsic inflammatory mechanisms may provide a regulatory system that is capable of influencing the neuronal microenvironment that affects neuronal survival. In this article, we address the evidence surrounding the interactions of dysfunctional astrocytes with neighboring neurons that may initiate a cascade of events that culminates with neuronal injury and the expression of the hallmark lesions of AD. Comprehensive knowledge of the molecular mechanisms underlying the participation of astrocytes in neurodegeneration could aid the development of therapies to restore proper astrocyte function that can be used in AD patients to prevent or alleviate the progression of the disease in a more efficient and comprehensive manner.     

凝血四项和血脂检测对评估绝经后2型糖尿病患者血管病变的临床意义*

目的探讨女性绝经后2型糖尿病(T2DM)患者凝血功能和血脂水平的变化及其与血管并发症的关系。方法分别检测(T2DM)组(n=205)和对照组(n=105)血浆凝血酶原时间(PT)、活化部分凝血酶原时间(APTT)、凝血酶时间(TT)、纤维蛋白原(FIB)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-c)、低密度脂蛋白胆固醇(LDL-c)和甘油三酯(TG)。结果 (1)T2DM组与对照组比较,无血管病变者PT、APTT显著下降(t=2.139、1.982,P0.05),FIB显著上升(t=2.138,P0.05);伴血管病变组PT、APTT和TT均显著下降(t=8.554、6.263和4.852,P0.01),FIB水平显著上升(t=3.537,P0.01)。(2)T2DM组与对照组比较,无血管病变和伴血管病变组TG、TC和LDL-C均显著升高(t=2.226、2.096和2.223,P0.05;t=4.940、3.055和3.106,P0.01),T2DM组组内比较,6.256,P0.05)。结论分析凝血四项和血脂水平对把握病情、诊断血管病变、指导治疗及预防糖尿病并发症有重要意义,故应尽早实施监测。     

Introduction and overview of the special issue “Brain imaging and aging”: The new era of neuroimaging in aging research

It is well known that the brain is one of the organs particularly affected by aging in terms of function, relative to the gastrointestinal tract and liver, which exhibit less functional decline. There is also a wide range of age-related neurological disorders such as stroke, Alzheimer’s disease, and Parkinson’s disease. Therefore, it is very important to understand the relationship between functional age-related change and neurological dysfunction. Neuroimaging techniques including magnetic resonance imaging and positron emission tomography have been significantly improved over recent years. Many physicians and researchers have investigated various mechanisms of age-related cerebral change and associated neurological disorders using neuroimaging techniques. In this special issue of Ageing Research Reviews, we focus on cerebral- and neuro-imaging, which are a range of tools used to visualize structure, functions, and pathogenic molecules in the nervous system. In addition, we summarize several review articles about the history, present values, and future perspectives of neuroimaging modalities.     

人羊膜上皮细胞移植改善AD样病变模型大鼠学习记忆能力

目的:观察人羊膜上皮细胞(h AECs)对阿尔茨海默病(AD)样病变大鼠模型的治疗效应。方法:采用胰蛋白酶消化法分离h AECs,流式细胞术分析表型。48只雄性SD大鼠随机分为假手术组、模型组、培养基组和h AECs移植组,每组12只。采用双侧脑室注入脂多糖(LPS)复制AD样病变大鼠模型。AD样病变大鼠海马区移植5×105个h AECs。细胞移植后2周,Morris水迷宫试验观察行为学变化,HE和硫磺素S染色观察海马病理变化,免疫组化染色检测β-淀粉样蛋白42(Aβ42)、Tau蛋白和乙酰胆碱(ACh)的变化,流式细胞术检测外周血T淋巴细胞亚群的变化,流式微球阵列捕获技术(cytometric bead array,CBA)检测血清细胞因子含量,免疫荧光染色检测海马区人细胞核抗原阳性细胞及其神经元特异性核蛋白(Neu N)的表达。结果:与模型组和培养基组比较,h AECs移植组大鼠逃避潜伏期明显缩短(P0.01),跨域平台次数明显增加(P0.05);海马神经元病损减轻,Aβ沉积减轻(P0.05),磷酸化Tau蛋白水平下降(P0.05),ACh增加(P0.05);外周血Th1和Th17细胞百分比下降(P0.05),而Th2和Treg细胞升高(P0.05);IL-2和IFN-γ水平下调(P0.05),而IL-4上调(P0.05);移植区可见h AECs,并表达Neu N。结论:h AECs可明显改善AD样病变模型大鼠空间辨别性学习记忆能力,减轻海马病理损伤,其免疫调节效应可能发挥重要作用。     

电针对SAMP8小鼠行为学及APP mRNA和BACE-1 mRNA影响

目的　探讨电针对SAMP8 小鼠行为学及淀粉样前体蛋白( amyloid precursor protein, APP) 和APP切割酶1(B site APP cleaving enzyme1, BACE-1)的影响,为临床治疗阿尔茨海默病病提供新的途径。 方法　将快速老化模型小鼠(SAMP8) 60只随机分成模型组、电针组和西药组,每组20只,正常老化小鼠 (SAMR1) 20只作为正常组。电针组电针刺激“百会”、 “肾俞”、“内关”、“大椎”穴;西药物组给予石杉碱甲 0.02 mg/kg剂量灌胃;正常组和模型组不给予治疗。治疗 20 d 后,用 Morris 水迷宫检测小鼠学习记忆能力,免疫组化定性检测小鼠海马APP和 BACE-1蛋白的表达,进一步实时荧光定量 PCR法测定APP mRNA和 BACE-1 mRNA 的表达。 结果　与模型组比较,西药组与电针组逃避潜伏期缩短,有效区停留时间和及跨越平台次数均显著增加(P＜0.05),电针组APP mRNA 和 BACE-1 mRNA 相对表达量显著减少(P<0.05) 。 结论　电针可能抑制 SAMP8 小鼠脑内APP mRNA and BACE-1 mRNA表达,减少Aβ 生成,改善其学习记忆障碍。     

White Matter Changes in Dementia: Role of Impaired Drainage of Interstitial Fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.