不同剂量多奈哌齐对阿尔茨海默病患者认知功能及血清IGF-1水平的影响

目的探讨不同剂量多奈哌齐对阿尔茨海默病(AD)患者认知功能与血清胰岛素样生长因子-1(IGF-1)水平的影响。方法选取四川省科学城医院2016年9月至2017年8月收治的AD患者96例为研究对象,按照随机数字表法分为低剂量组、中剂量组、高剂量组3组,每组32例。低剂量组每次口服2.5 mg多奈哌齐,中剂量组每次口服5.0 mg多奈哌齐,高剂量组每次口服10.0 mg多奈哌齐。比较3组患者治疗前,治疗后3、6、9个月的简易精神状态量表(MMSE量表)、阿尔茨海默病评定量表认知分量表(ADAS-cog量表)评分及血清IGF-1水平。结果低剂量组治疗前与治疗后3、6、9个月的MMSE量表评分、ADAS-cog量表评分、IGF-1水平比较,差异均无统计学意义(P>0.05)。中剂量组与高剂量组治疗后6、9个月的MMSE量表评分、ADAS-cog量表评分、IGF-1水平与治疗前比较,差异均有统计学意义(P<0.05),且高剂量组治疗后6、9个月的MMSE量表评分、IGF-1水平高于中剂量组、低剂量组,ADAS-cog量表评分低于中剂量组、低剂量组,差异均有统计学意义(P<0.05)。结论多奈哌齐可显著改善AD患者认知功能、提升日常生活能力和升高血清IGF-1水平,且存在剂量相关效应,高剂量多奈哌齐疗效更佳。     

Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier

BACKGROUND: Monocyte/macrophages are known to infiltrate the brain of patients with HIV-1 encephalitis (HIVE). In Alzheimer's disease brain, the origin of activated microglia has not been determined. MATERIALS AND METHODS: We employed the antigen retrieval technique, immunocytochemistry, immunofluorescense, and confocal microscopy to identify macrophages and microglia in relation to amyloid-beta plaques and the blood-brain barrier in autopsy brain tissues from patients with Alzheimer's disease (AD) and HIVE. RESULTS: In both conditions, cyclooxygenase-2 positive macrophages and, to a lesser degree, T and B cells infiltrate brain perivascular spaces and neuropil. The macrophages are distinguishable from ramified microglia, and decorate the vessels at the sites of apparent of endothelial tight junction protein ZO-1 disruption. The macrophages also infiltrate amyloid-beta plaques, display intracellular amyloid-beta and are surrounded by amyloid-beta-free lacunae. Furthermore, the macrophages partially encircle the walls of amyloid-beta-containing vessels in amyloid angiopathy, and exhibit intracellular amyloid-beta but not paracellular lacunae. Significantly larger zones of fibrinogen leakage surround the microvessels in HIVE brain tissues compared with AD tissues (P = 0.034), and AD tissues have significantly greater leakage than control tissues (P = 0.0339). The AD group differs from a normal control age-matched group with respect to both the area occupied by CD68 (P = 0.03) and cyclooxygenase-2 immunoreactive cells (P = 0.004). CONCLUSION: In both HIVE and AD, blood-borne activated monocyte/macrophages and lymphocytes appear to migrate through a disrupted blood-brain barrier. The lacunae around macrophages in amyloid-beta plaques but not in vessel walls are consistent with the ability of macrophages to phagocytize and clear amyloid-beta deposits in vitro.     

Role of hippocampal CA1 atrophy in memory encoding deficits in amnestic Mild Cognitive Impairment

Identifying the specific substrates of memory deficits in early Alzheimer's disease would help to develop clinically-relevant therapies. The present study assesses the relationships between encoding versus retrieval deficits in patients with amnestic Mild Cognitive Impairment (aMCI) and atrophy specifically within the hippocampus and throughout the white matter. Twenty-two aMCI patients underwent T1-weighted MRI scans and neuropsychological testing. Grey matter and white matter segments obtained from the MRI images were each entered in correlation analyses, assessed only in the hippocampus for grey matter segments, with encoding and retrieval memory performances. For the grey matter segments, the resulting spmT correlation maps were then superimposed onto a 3D surface view of the hippocampus to identify the relative involvement of the different subfields, a method already used and validated elsewhere. Memory encoding deficits specifically correlated with CA1 subfield atrophy, while no relationship was found with white matter atrophy. In contrast, retrieval deficits were weakly related to hippocampal atrophy and did not involve a particular subfield, while they strongly correlated with loss of white matter, specifically in medial parietal and frontal areas. In aMCI patients, encoding impairment appears specifically related to atrophy of the CA1 hippocampal subfield, consistent with the predominance of encoding deficits and CA1 atrophy in aMCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network.     

Molecular simulation of the primary and secondary structures of the Aβ(1-42)-peptide of Alzheimer's disease

The major protein constituent of the deposits of Alzheimer's disease is the so-called amyloid β-peptide (Aβ) which was derived from proteolysis of a large transmembrane amyloid precursor protein. Some physicochemical and biological properties of the Aβ(1-42) peptide are described in this paper. Three functional areas of the soluble Aβ(1-42) peptide were found: (i) a lipophilic region in the middle of the peptide (Lys16 to Ala21), (ii) a second lipophilic core at the end (Lys28 to Val40), and (iii) polarized and charged, solvent-exposed areas. Using molecule coordinates found experimentally by NMR-solution spectroscopy, subsequent Gasteiger-MM⁺ geometry optimization led to the result that the first lipophilic core has an α-helical structure which is stabilized by intramolecular hydrogen-bonding forces. The result is a loop-like molecule. The second lipophilic core has a β-sheet structure, and is able to form long-ranged, noncovalent, mainly hydrophobic forces with other β-sheets of Aβ peptides. The β-strands run in an antiparallel direction. The aggregates are highly stable and ordered. The negatively charged, solvent-exposed residues are potential sites for a crosslinking with membrane-bound receptors. A perspective in drug research is the development of drugs that bind to individual β-sheets by noncovalent interactions, blocking the associations between the individual Aβ peptides and preventing the formation of amyloid aggregates. © 1998 John Wiley & Sons, Inc. Med Res Rev, 18, No. 6, 403–430, 1998.     

Microglia during development and aging

Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, and axonal degeneration. Changes in microglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microglia potentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging.