黑质神经元纤维缠结与老年步态障碍有关

Objective: Parkinsonian signs, especially gait impairment, are common and associated with morbidity and mortality in older persons. Our objective was to test the hypothesis that substantia nigra neurofibrillary tangles (NFTs) are related to parkinsonian signs in older persons with and without dementia. Methods: We studied 86 deceased older Catholic clergy without idiopathic Parkinson’s disease from the Religious Order Study, a longitudinal clinical-pathological study. Mean age at death was 85.3 years. Signs of gait disturbance, bradykinesia, rigidity, and tremor were assessed proximate to death using a modified Unified Parkinson’s Disease Rating Scale. Forty-micrometer paraffin-embedded sections of substantia nigra were bleached before tau immunohistochemistry and the optical disector was used to count NFTs. We used multivariable linear regression to examine parkinsonian signs as a function of nigra NFTs, controlling for age, sex, education, and cortical NFTs. Results: Substantia nigra NFTs were present in 67 of 86 persons (77.9% ). After controlling for age, sex, education, and cortical NFTs, nigra NFTs were related to gait impairment (p < 0.001), but not bradykinesia, rigidity, or tremor. Results were not confounded by dementia, Braak score, neuroleptic medication, cerebral infarcts, or Lewy bodies. Interpretation: NFTs in the substantia nigra are associated with gait impairment in older persons with and without dementia.

老年美籍非洲人和白人中的社会资源和认知功能减退情况

Objective: To examine the relation of social resources and cognitive decline in older adults. Methods: Data are from the Chicago Health and Aging Project, an epidemiologic study of risk factors for Alzheimer disease (AD) and other common conditions in a geographically defined population of older persons. The sample consisted of 6,102 non-Hispanic African Americans (61.2% ) and whites, aged ≥ 65, who underwent up to three interviews during an average of 5.3 years of fo llow-up. Each interview included administration of four cognitive function tes ts from which a composite measure of cognition was formed. Social networks were based on the number of children, relatives, and friends seen at least once a mon th. Social engagement was measured with four items related to social and product ive activity. Results: Higher number of social networks and level of social enga gement were positively correlated with initial level of cognitive function (netw orks estimate = 0.003, engagement estimate = 0.060, both p < 0.001). Both resour ces were also associated with a reduced rate of cognitive decline. A high (90th percentile) number of networks reduced the rate of decline by 39% compared to a low level (10th percentile), and high social engagement reduced decline by 91 % . These relations remained after controlling for socioeconomic status, cognit ive activity, physical activity, depressive symptoms, and chronic medical condit ions. Conclusions: Greater social resources, as defined by social networks and s ocial engagement, are associated with reduced cognitive decline in old age.

淀粉样蛋白介导的载脂蛋白E(APOE)e4等位基因与老年人认知功能的联系

Background: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. Abstract:Objective: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. Methods: There were 44 subjects with clinically diagnosed Alzheimer’s disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. Results: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60%and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50%and was no longer significant after controlling for the effect of amyloid load. Conclusion: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.

内隐记忆与阿尔茨海默病的神经病理

Explicit memory failure is the defining cognitive feature of Alzheimer’s disease and relates to the hallmark neuropathological features (plaques and tangles) of this illness. However, a pattern of preserved and impaired implicit memory has been found in Alzheimer’s disease patients that may be explained by the association between the processing demands of certain implicit tests and the level of regional Alzheimer’s disease neuropathology. In this study, we tested the hypothesis that these neuropathological features are related to implicit memory -measured by repetition priming -in a test that emphasized conceptual (or meaning-based) cognitive processing, and that the pathological changes are not related to implicit memory in a repetition priming test that emphasized perceptual (or sensory-based)-cognitive processing. Subjects were older nuns, priests and brothers participating in the Religious Orders Study who agreed to annual neurological and neuropsychological evaluation for Alzheimer’s disease and common neurological conditions of ageing, and brain autopsy at time of death. Explicit memory was measured by seven tests of episodic recall and recognition and converted to a previously established summary measure. Implicit memory was measured by four repetition priming tests. One test, category exemplar priming, emphasized conceptual, or meaning-based cognitive processing. A second test, word-identification priming, emphasized perceptual, or sensory-based cognitive processing. Two additional priming tests, picture-naming and word-stem completion, invoke both conceptual and perceptual processes. Neuritic and diffuse plaques, and neurofibrillary tangles identified by Bielschowsky silver stain, were quantified from five regions separately (frontal, parietal, temporal, entorhinal cortex and the hippocampus) and converted to a previously established summary measure. In linear regression analyses -controlling for age, sex and education-higher levels of Alzheimer’s disease neuropathology were related to lower levels of explicit memory proximate to death. Higher levels of neuropathology were also related to lower levels of priming on the category-exemplar test, but were not related to levels of priming on the word-identification, picturenaming, or word-stem completion tests. The results suggest that hallmark indices of Alzheimer’s disease neuropathology are associated with performance on priming tests to the extent that conceptual, but not perceptual, processing resources are required.

DNA Methylation and Uveal Melanoma

Objective： The objective of the study was to summarize the role of DNA methylation in the development and metastasis of uveal melanoma （UM）. Data Sources： The relevant studies in MEDLINE were searched. Study Selection： In this review, we performed a comprehensive literature search in MEDLINE using ＂uveal melanoma＂ AND （＂DNA methylation＂ OR ＂epigenetics＂） for original research/review articles published before February 2018 on the relationship between DNA methylation and UM. References of the retrieved studies were also examined to search for potentially relevant papers. Results： Previous studies on the relationship between DNA methylation and UM covered many genes including tumor suppressor genes （TSGs）, cyclin-dependent kinase genes, and other genes. Among them, the TSG genes such as RASSFIA and p16INK4a, which encodes a cyclin-dependent kinase inhibitor, are relatively well-studied genes. Specifically, a high percentage of promoter methylation of RASSF1A was observed in UM cell lines and/or patients with UM. Promoter methylation of RASSFIA was also associated with the development of metastasis. Similarly, a high percentage of promoter hypernlethylation of p16INK4a was found in UM cell lines. DNA promoter methylation can control the expression of p16INK4a, which affect cell growth, migration, and invasion in UM. Many other genes might also be involved in the pathogenesis of UM such as tile Ras and EF-hand domain containing （RASEF） gene, RAB31, hTERT, embryonal fyn-associated substrate, and deleted in split-hand/split-foot 1. Conclusions： Our review reveals the complex mechanisms underlying the tumorigenesis of UM and highlights the great needs of future studies to discover more genes/5＇-C-phosphate-G-3＇ sites contributing to the development/metastasis of U M and explore the mechanisms through which epigenetic changes exert their function in UM.