磁共振技术在轻度认知障碍与阿尔茨海默病中的研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是当今老年人最常见的一种原发性神经退行性疾病。其主要病理学特征表现为神经元的脱失、神经纤维缠结及老年斑形成。轻度认知障碍(mild cognitive impairment,MCI)被认为是AD及其他老年痴呆症的前驱阶段,可进一步转化成AD,且MCI与AD有着相似的病理变化。随着MCI和AD患病数的逐年增加,其给患者家属及社会增添了巨大负担,因此,对MCI和AD作出早期诊断变得尤为重要。然而,MCI和AD早期的临床表现并不突出,且实验室检查也缺乏足够的特异性,当临床医生做出明确诊断时,多数患者已处于AD的中晚期。近年来,随着磁共振技术的不断发展,多种磁共振技术已广泛地应用于MCI和AD的研究中,并为MCI及AD的早期诊断提供了重要的影像学依据。本文分别从结构性磁共振(s MRI)、静息态f MRI、磁共振弥散张量成像(DTI)、磁共振波谱成像(MRS)、磁敏感加权成像(SWI)及MRI分子影像几个方面,阐述多种磁共振技术在MCI和AD研究中的进展。     

基于体素的形态测量学在阿尔茨海默病及轻度认知功能障碍研究中的应用

阿尔茨海默病(Alzheimer's disease,AD)是发生于老年和老年前期、以进行性认知功能障碍和行为异常为特征的中枢神经系统退行性疾病,是老年痴呆中最常见类型。轻度认知功能障碍(mild cognitive impairment,MCI)是介于正常衰老和痴呆之间的一种中间状态,指有轻度的记忆或认知损伤,但尚未达到痴呆程度的一种状态,日常生活和社会功能不受影响,其中很大一部分患者最终进展为AD。临床诊断AD患者多已达中晚期,为了能早期诊断AD及预测MCI的转归,有关AD的生物学标注物的研究成为近年来的科研热点。AD患者颅脑的大体病理特征为脑萎缩,其萎缩有别于正常老龄化所致的退行性改变,有其自身特点,这种特定形式的萎缩有可能成为AD早期诊断的生物学标志物。基于体素的形态测量学(voxel-based morphometry,VBM)是一种基于像素水平对脑核磁图像进行自动、全面、客观分析的技术,可以定量分析全脑结构、刻画出局部脑区结构特征,是一种较好的脑形态分析工具,广泛用于阿尔茨海默病及轻度认知功能障碍的研究中,本文综述了近年来其研究进展,期望为临床及科研提供参考。     

Dihydrotestosterone treatment delays the conversion from mild cognitive impairment to Alzheimer's disease in SAMP8 mice

The senescence-accelerated-prone mouse 8 (SAMP8) has been proposed as a suitable, naturally derived animal model for Alzheimer's disease (AD). In the current study, we focus on the problem whether SAMP8 mice show abnormal behavioral and neuropathological signs before they present the characteristic of AD. Our results demonstrated that given the presence of the senescent, behavioral and neuropathological characteristics, the “middle-aged” SAMP8 mice appear to be a suitable and naturally derived animal model for MCI basic research. There is relatively less evidence that androgen may be involved in the pathogenesis of AD. We determined testosterone (T) levels of SAMR1 and SAMP8 mice and found that the marked age-related decrease in serum androgen levels may be one of the risk factors for Alzheimer's dementia. We also evaluated the interventional effect on MCI phase by dihydrotestosterone (DHT) in male SAMP8 mice and found that timely and appropriate androgen intervention can postpone the onset and improve the symptoms of dementia.     

Oxidative stress and APO E polymorphisms in Alzheimer's disease and in mild cognitive impairment

Abstract

A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients.

APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis.

We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p < 0.0001) and MCI patients (p < 0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p < 0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p < 0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p < 0.05) superoxide dismutase activity with respect to non-E4 carriers.

This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor.     

Protein interaction network for Alzheimer's disease using computational approach

Alzheimer''s disease (AD) is the most common form of dementia. It is the sixth leading cause of death in old age people. Despiterecent advances in the field of drug design, the medical treatment for the disease is purely symptomatic and hardly effective. Thusthere is a need to understand the molecular mechanism behind the disease in order to improve the drug aspects of the disease. Weprovided two contributions in the field of proteomics in drug design. First, we have constructed a protein-protein interactionnetwork for Alzheimer''s disease reviewed proteins with 1412 interactions predicted among 969 proteins. Second, the diseaseproteins were given confidence scores to prioritize and then analyzed for their homology nature with respect to paralogs andhomologs. The homology persisted with the mouse giving a basis for drug design phase. The method will create a new drug designtechnique in the field of bioinformatics by linking drug design process with protein-protein interactions via signal pathways. Thismethod can be improvised for other diseases in future.     

Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

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Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment

Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports have not examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and non-demented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease.     

Nucleic acid oxidation: an early feature of Alzheimer's disease

Studies of oxidative damage during the progression of Alzheimer's disease (AD) suggest its central role in disease pathogenesis. To investigate levels of nucleic acid oxidation in both early and late stages of AD, levels of multiple base adducts were quantified in nuclear and mitochondrial DNA from the superior and middle temporal gyri (SMTG), inferior parietal lobule (IPL), and cerebellum (CER) of age‐matched normal control subjects, subjects with mild cognitive impairment, preclinical AD, late‐stage AD, and non‐AD neurological disorders (diseased control; DC) using gas chromatography/mass spectrometry. Median levels of multiple DNA adducts in nuclear and mitochondrial DNA were significantly (p ≤ 0.05) elevated in the SMTG, IPL, and CER in multiple stages of AD and in DC subjects. Elevated levels of fapyguanine and fapyadenine in mitochondrial DNA suggest a hypoxic environment early in the progression of AD and in DC subjects. Overall, these data suggest that oxidative damage is an early event not only in the pathogenesis of AD but is also present in neurodegenerative diseases in general.

     

Selenium status in elderly: Relation to cognitive decline

Studies show that decreased antioxidant system is related to cognitive decline. Thus we aimed to measure selenium (Se) status in Alzheimer's disease (AD) and mild cognitive impairment (MCI) elderly and compared them with a control group (CG). 27 AD, 17 MCI and 28 control elderly were evaluated. Se concentration was determined in plasma and erythrocyte by using hydride generation atomic absorption spectroscopy. Erythrocyte Se concentration in AD group was lower than CG (43.73 ± 23.02 μg/L and 79.15 ± 46.37 μg/L; p = 0.001), but not statistically different from MCI group (63.97 ± 18.26 μg/L; p = 0.156). AD group exhibited the lowest plasma Se level (34.49 ± 19.94 μg/L) when compared to MCI (61.36 ± 16.08 μg/L; p = 0.000) and to CG (50.99 ± 21.06 μg/L; p = 0.010). It is observed that erythrocyte Se decreases as cognition function does. Since erythrocyte reflects longer-term nutritional status, the data point to the importance of the relation between Se exposure and cognitive function. Our findings suggest that the deficiency of Se may contribute to cognitive decline among aging people.     

Alzheimer's disease care and management: role of information technology

Alzheimer's disease (AD) an ailment that is supposed to affect people in old age. There are evidences that it might affect others also. The number of elders is increasing as the average life expectancy is increasing. AD afflicts its patients with the dementia and AD might increase in malignance over time. People with cognitive disabilities can be overwhelmed through cognitive prosthetics. With the help of information technology we can enhance the quality of life. Significant achievements are possible with an interdisciplinary approach that includes genomic, genetic, technological and therapeutic measures. The combination and coordination of Bioinformatics facilitates generation of various diagnostic tools for the people who are suffering from Alzheimer's disease. These tools help the care providers also. In this article, we emphasize the literature regarding the use of technology and its methodologies to improve the quality of care for the people with Alzheimer's disease.     

Neuroendocrine immunity in patients with Alzheimer's disease: toward translational epigenetics

The emerging domain of epigenetics in molecular medicine finds application for a variety of patient populations. Here, we present fundamental neuroendocrine immune evidence obtained in patients with senile dementia of the Alzheimer's type (sDAT), and discuss the implications of these data from the viewpoint of translational epigenetics of Alzheimer's disease. We followed 18 subjects with mild sDAT treated with acetylcholinesterase inhibitors, and 10 control subjects matched for age in a repeated measure design every six months for 18 months. We monitored psychosocial profile (Mini-Mental State Examination, Functional Assessment Staging, Independence in Activities of Daily Living, Depression, Profile of Moods States) in parallel to immunophenotypic parameters of T cell subpopulations by flow cytometry. Based on change in the mini-mental state score at entry and at 18 months, patients with sDAT were assigned to a "fast progression" (delta greater than 2 points) or to a "slow progression" group (delta less than or equal to 2 points). The change in circulating activated T cells (CD3+Dr+) with time in patients with sDAT was significantly inversely correlated with the change in time in natural killer (NK) cytotoxic activity to cortisol modulation in these patients, which was greater in patients with fast progression, compared to slow progression sDAT. These data indicate underlying neuroendocrine immune processes during progression of sDAT. Our observations suggest that psychoimmune measures such as those we have monitored in this study provide relevant information about the evolving physiological modulation in patients with sDAT during progression of Alzheimer's disease, and point to new or improved translational epigenetic treatment interventions.     

New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc

The molecular determinants of Alzheimer''s (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca²⁺) and zinc (Zn²⁺). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-β dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca²⁺ and Zn²⁺ dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca²⁺ and Zn²⁺ rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca²⁺ and Zn²⁺ dyshomeostasis may offer a great opportunity for disease-modifying strategies.     

Platelet biomarkers identifying mild cognitive impairment in type 2 diabetes patients

Type 2 diabetes mellitus (T2DM) is an independent risk factor of Alzheimer''s disease (AD). Therefore, identifying periphery biomarkers correlated with mild cognitive impairment (MCI) is of importance for early diagnosis of AD. Here, we performed platelet proteomics in T2DM patients with MCI (T2DM‐MCI) and without MCI (T2DM‐nMCI). Pearson analysis of the omics data with MMSE (mini‐mental state examination), Aβ1‐42/Aβ1‐40 (β‐amyloid), and rGSK‐3β(T/S9) (total to Serine‐9‐phosphorylated glycogen synthase kinase‐3β) revealed that mitophagy/autophagy‐, insulin signaling‐, and glycolysis/gluconeogenesis pathways‐related proteins were most significantly involved. Among them, only the increase of optineurin, an autophagy‐related protein, was simultaneously correlated with the reduced MMSE score, and the increased Aβ1‐42/Aβ1‐40 and rGSK‐3β(T/S9), and the optineurin alone could discriminate T2DM‐MCI from T2DM‐nMCI. Combination of the elevated platelet optineurin and rGSK‐3β(T/S9) enhanced the MCI‐discriminating efficiency with AUC of 0.927, specificity of 86.7%, sensitivity of 85.3%, and accuracy of 0.859, which is promising for predicting cognitive decline in T2DM patients.     

Involvement of brain oxidation in the cognitive impairment in a triple transgenic mouse model of Alzheimer's disease: Noninvasive measurement of the brain redox state by magnetic resonance imaging

Abstract

Oxidative stress is considered to be related to the onset and/or progression of Alzheimer's disease (AD), but there is insufficient evidence of its role(s). In this study, we evaluated the relationships between the brain redox state and cognitive function using a triple transgenic mouse model of AD (3 × Tg-AD mouse). One group of 3 × Tg-AD mice started to receive an α-tocopherol-supplemented diet at 2 months of age and another group of 3 × Tg-AD mice was fed a normal diet. The levels of α-tocopherol, reduced glutathione, oxidized glutathione, and lipid peroxidation were decreased in the cerebral cortex and hippocampus at 4 months of age in the 3 × Tg-AD mice fed a normal diet. These reductions were abrogated by the supplementation of α-tocopherol in the diet. During Morris water maze testing, the 3 × Tg-AD mice did not exhibit cognitive impairment at 4 months of age, but started to show cognitive dysfunction at 6 months of age, and α-tocopherol supplementation suppressed this dysfunction. Magnetic resonance imaging (MRI) using 3-hydroxymethyl-proxyl as a probe showed decreases in the signal intensity in the brains of 3 × Tg-AD mice at 4 months of age, and this reduction was clearly attenuated by α-tocopherol supplementation. Taken together, these findings suggest that oxidative stress can be associated with the cognitive impairment in 3 × Tg-AD mice. Furthermore, MRI might be a powerful tool to noninvasively evaluate the increases in reactive radicals, especially those occurring during the early stages of AD.     

Adult hippocampal neurogenesis in aging and Alzheimer's disease

Adult neurogenesis occurs in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles. This process is highly regulated by intrinsic and extrinsic factors, which may control the proliferation and/or maturation of neural progenitor cells. Adult-born neurons are integrated in preexisting networks and may have functional implications for adult brain. Here we attempt to summarize relevant findings concerning the physiological role of adult neurogenesis mainly focused on the subgranular zone, and to discuss the reduced neurogenesis observed during aging and the factors that have been involved in this phenomenon. Finally, we focus on hippocampal neurogenesis in Alzheimer's disease, reviewing animal models of the disease used for the study of this process and the conclusions that have been drawn in this context.     

A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein.

It is well established that mutations in the presenilin 1 and 2 genes cause the majority of early onset Alzheimer's disease (AD). However, our understanding of the cellular functions of the proteins they encode remains rudimentary. Knowledge of proteins with which the presenilins interact should lead to a better understanding of presenilin function in normal and disease states. We report here the identification of a calcium-binding protein, calmyrin, that interacts preferentially with presenilin 2 (PS2). Calmyrin is myristoylated, membrane-associated, and colocalizes with PS2 when the two proteins are overexpressed in HeLa cells. Yeast two-hybrid liquid assays, affinity chromatography, and coimmunoprecipitation experiments confirm binding between PS2 and calmyrin. Functionally, calmyrin and PS2 increase cell death when cotransfected into HeLa cells. These results allude to several provocative possibilities for a dynamic role of calmyrin in signaling, cell death, and AD.     

Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease

Recent studies show that in Alzheimer''s disease (AD), alterations in neurogenesis contribute to the neurodegenerative process. Neurodegeneration in AD has been associated with aberrant signaling through the cyclin-dependent kinase-5 (CDK5) pathway via its activators p35/p25; however, the role of CDK5 in the mechanisms of defective adult neurogenesis in AD is unknown. First, to study AD-like abnormal activation of CDK5 signaling in an in vitro model of neurogenesis, neuronal progenitor cells (NPCs) were infected with a viral vector expressing p35, and exposed to amyloid-β protein (Aβ₁₋₄₂). These conditions resulted in impaired maturation and neurite outgrowth in vitro, and these effects were reversed by pharmacological or genetic inhibition of CDK5. Similarly, neurogenesis was impaired in a transgenic mouse model of AD that expresses high levels of amyloid precursor protein (APP), and this effect was reversed in transgenic mice crossed with a CDK5 heterozygous-deficient mouse line. A similar rescue effect was observed in APP transgenic mice treated with Roscovitine, a pharmacological inhibitor of CDK5. Taken together, these data suggest that the CDK5 signaling pathway has a critical role in maintaining the integrity of NPCs and neuronal maturation in the adult hippocampus. Moreover, potential therapeutic approaches could focus on modulating the aberrant activity of CDK5 to target the neurogenic and neurodegenerative alterations in AD.     

Effects of Gingko biloba supplementation in Alzheimer's disease patients receiving cholinesterase inhibitors: Data from the ICTUS study

Ginkgo biloba (Gb) is currently the most investigated and adopted herbal remedy for cognitive disorders and Alzheimer's disease (AD). Nevertheless, its efficacy in the prevention and treatment of dementia still remains controversial. Specifically, the added effects of Gb in subjects already receiving “conventional” anti-dementia treatments have been to date very scarcely investigated. We evaluated whether the use of Gb is associated with additional cognitive and functional benefit in AD patients already in treatment with cholinesterase inhibitors (ChEIs).Data are from mild to moderate AD patients under ChEI treatment recruited in the Impact of Cholinergic Treatment USe (ICTUS) study. Mixed model analyses were performed to measure six-monthly modifications in the Mini Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score, and the Activities of Daily Living (ADL) scale over a follow-up of 1 year according to the additional Gb supplementation.A total of 828 subjects were considered for the present analyses. Significantly different modifications at the MMSE score over the 12-month follow-up were reported between patients on combined therapy compared to those only taking ChEIs. On the contrary, the modification of the ADAS-Cog score between the two groups did not show statistically significant differences, although similar trends were noticed. No significant modifications of the two adopted outcome measures were observed at the mid-term 6-month evaluation. The modifications over time of the ADL score did not show statistically significant differences between the two groups of interest.Our findings suggest that Gb may provide some added cognitive benefits in AD patients already under ChEIs treatment. The clinical meaningfulness of such effects remains to be confirmed and clarified.     

多奈哌齐治疗阿尔兹海默症患者的临床剂量使用探讨

目的:评价多奈哌齐治疗阿尔兹海默症(AD)的疗效及疗效与用药剂量的关系,探讨检测血清中胰岛素样生长因子-I(IGF-I)来指导治疗剂量的可行性。方法:87例轻中度的AD患者,患者使用5 mg/d多奈哌齐疗效不佳。在增加剂量之前,根据血清胰岛素样生长因子-I(IGF-I)水平和简易智力状态检查表(MMSE)得分之间的一致性,将患者分为3组。A组:n=27,IGF-I≤99ng/m L,MMSE≤37;B组:n=33,IGF-I≤99 ng/m L,MMSE18;C组:n=27,IGF-I99 ng/m L,MMSE18。A、B组中,血清IGF-I水平显著低于C组。试验开始后将多奈哌齐的剂量从5 mg/d增加到10 mg/d,服用12周后,观察血清IGF-I水平同MMSE和阿尔兹海默症评定量表(ADAS)得分的相关性及三组患者的临床改善情况。结果:血清IGF-I水平同认知功能有明显相关性。IGF-I同MMSE正相关(r=0.478,P=0.036),IGF-I同ADAS得分负相关(r=-0.464,P=0.029)。增加多奈哌齐(10 mg/d)剂量治疗后,只有A组患者MMSE得到显著改善。A组患者对治疗的敏感性显著高于B、C组患者。结论:血清中IGF-I水平和MMSE分值可以做为一种标志物,判断对低剂量多奈哌齐(5 mg/d)无效的轻中度AD患者,能否采用高剂量多奈哌齐(10 mg/d)进行治疗。