Cognitive reserve in neuropsychiatry

BACKGROUND: The idea that superior cognitive function acts as a protective factor against dementia and the consequences of head injury is well established. Here we suggest the hypothesis that cognitive reserve is also important in neuropsychiatric disorders including schizophrenia, bipolar disorder and depression. METHOD: We review the history of passive and active models of reserve, and apply the concept to neuropsychiatric disorders. Schizophrenia is used as an exemplar because the effects of premorbid IQ and cognitive function in this disorder have been extensively studied. RESULTS: Cognitive reserve may impact on neuropsychiatric disorders in three ways: by affecting the risk for developing the disorder, in the expression of symptoms within disorders, and in patients' functional outcome. Cognitive failure below a certain threshold may alone, or in combination with common psychiatric symptoms, produce neuropsychiatric syndromes. CONCLUSIONS: Consideration of cognitive reserve may considerably improve our understanding of individual differences in the causes and consequences of neuropsychiatric disorders. For these reasons, the concept of cognitive reserve should be incorporated in future studies of neuropsychiatric disorder. It may be possible to enhance cognitive reserve through pharmacological or non-pharmacological means, such as education, neurocognitive activation or other treatment programmes.     

Cognitive reserve and the neurobiology of cognitive aging

A hypothetical construct of "cognitive reserve" is widely used to explain how, in the face of neurodegenerative changes that are similar in nature and extent, individuals vary considerably in the severity of cognitive aging and clinical dementia. Intelligence, education and occupational level are believed to be major active components of cognitive reserve. Here, we summarize the main features of cognitive aging and their neuropathological correlates. We describe the neurobiology of cognitive aging and conclude that perturbations of neural health attributable to oxidative stress and inflammatory processes alone are insufficient to distinguish cognitive aging from Alzheimer's disease. We introduce the concept of cognitive reserve and illustrate its utility in explaining individual differences in cognitive aging. Structural and functional brain imaging studies suggest plausible neural substrates of cognitive reserve, probably involving processes that support neuroplasticity in the aging brain. The cognitive reserve hypothesis conforms with reported associations between early and mid life lifestyle choices, early education, lifelong dietary habit, leisure pursuits and the retention of late life mental ability.     

Cognitive reserve and anosognosia in questionable and mild dementia

Cognitive reserve (CR) theory posits that the clinical presentation of individuals with the same brain disease varies based upon premorbid variables (e.g., education, occupation, reading ability). Anosognosia (decreased insight regarding one's deficits) is common in dementia and has implications for safety, treatment, and caregiver burden. The current study examined the role of CR in anosognosia in individuals with mild dementia. Participants were individuals diagnosed with questionable or mild dementia (Clinical Dementia Rating 0.5 or 1) after neuropsychological evaluation. Anosognosia was measured by informant–patient discrepancy on the Cognitive Difficulties Scale. High and Low CR groups were created based upon reading performance. Low CR showed greater anosognosia than High CR. Anosognosia was associated with reduced reading performance, even after controlling for global cognitive decline. These findings suggest CR is related to anosognosia in questionable and mild dementia, and have clinical implications for the assessment of awareness in dementia.     

Cognitive reserve, age, and neuropsychological performance in healthy participants

The first aim of this study was to explore the relation between cognitive reserve, age, and neuropsychological functioning in a healthy sample; and second, to determine the risk of showing cognitive deficits as a function of cognitive reserve. One hundred forty-six healthy participants between the ages of 20 and 79 were submitted to neuropsychological assessment, focusing on attention, memory, visuo-construction, conceptualization and reasoning. Premorbid IQ as measured with the Wechsler Adult Intelligence Scale Vocabulary subtest was used as a proxy of cognitive reserve. Multivariate regression analysis with age and premorbid IQ as explanatory factors revealed a significant effect in all neuropsychological tests. Logistic regression revealed that participants with low cognitive reserve were more likely to obtain deficient scores (≤1.5 SD below the mean) in the cognitive domains of attention (odds ratio [OR], 3.13; 95% confidence interval [CI], 1.05-9.29), memory (OR, 6.17; 95% CI, 1.69-22.61) and global functioning (OR, 6.44; 95% CI, 2.56-16.22) than participants with high cognitive reserve. Results suggest that cognitive reserve acts as a protective factor against the expression of cognitive decline related to age in healthy individuals.     

Cognitive function in families with exceptional survival

The authors investigated whether cognitive function may be used as an endophenotype for longevity by assessing the cognitive performance of a family-based cohort consisting of 1380 individuals from 283 families recruited for exceptional survival in field centers in Boston, New York, Pittsburgh, and Denmark. Cognitive performance was assessed in the combined offspring of the Long Life Family Study (LLFS) probands and their LLFS siblings as compared with their spouses' cognitive performance. Our results indicate that the combined offspring of the LLFS probands and their siblings achieve significantly higher scores on both digit forward and backward tasks (p = 5 10^-5 and p = 8 10^-4 respectively) as well as on a verbal fluency task (p = 0.008) when compared with their spouse controls. No differences between groups were found for the other cognitive tests assessed. We conclude that LLFS family members in the offspring generation demonstrate significantly better performance on multiple tasks requiring attention, working memory, and semantic processing when compared with individuals without a family history of exceptional survival, suggesting that cognitive performance may serve as an important endophenotype for longevity.     

Cognitive reserve and mortality in dementia: the role of cognition, functional ability and depression

OBJECTIVE: This study examined whether dementia patients with greater cognitive reserve had increased mortality rates, and whether this association was different across strata of cognition, functional ability and depression. METHODS: In the community-based Amsterdam Study of the Elderly, 261 non-institutionalized dementia patients, identified using the Geriatric Mental State Schedule (GMS), were followed for an average of 55.5 months after which mortality data were obtained. Cognitive reserve was indicated by years of education and pre-morbid intelligence (measured using the Dutch Adult Reading Test). Cognition, functional ability and depression were indicated by Mini-Mental State scores, ADL and IADL measurements and GMS depressive syndrome, respectively. RESULTS: During the follow-up 146 persons (55.9%) died. Cox regression analyses showed that more highly educated dementia patients had higher mortality rates, only if they had low MMSE scores or if they had a concurrent depression. Pre-morbid intelligence was associated with a higher mortality rate, independent of cognition, but this association was much stronger among patients with depression. The positive association between education or intelligence and mortality was not modified by functional disabilities. CONCLUSIONS: The results suggest that dementia patients with greater cognitive reserve have increased mortality rates, only if the disease has progressed to such an extent that clinical symptoms are more severe. In this respect, the reserve hypothesis needs a modification. Depression in dementia patients with greater cognitive reserve may reflect a subgroup of patients with poor prognosis.     

miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy

Identification of factors to detect chemotherapy-resistant tumours at diagnosis is a first priority for risk-adapted therapy in the oncology of children and young adults, where more individualized, effective, and less toxic treatments are highly desirable. In this study, we analysed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcomes in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWSs by using the Agilent human miRNA microarray v.2 and/or qRT-PCR. Statistical power of the samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of five miRNAs (miR-34a, miR-23a, miR-92a, miR-490-3p, and miR-130b) as an independent predictor of risk for disease progression and survival. Validation analysis in the extended sample set indicated that both miR-34a and miR-490-3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis. Patients with the highest expression of miR-34a did not experience adverse events in 5 years; in contrast, patients with the lowest expression recurred within 2 years. High expression of miR34a can be detected also in paraffin-embedded tissues by in situ hybridization, thus contributing to an easy routine evaluation of this miRNA. Functional analysis of miR-34a in EWS cell lines indicated that when miR-34a expression was enforced, cells were less proliferative, less malignant, and sensitized to doxorubicin and vincristine. Expression of miR-34a could be increased in p53wt cells by treatment with nutlin-3a. Accordingly, nutlin-3a synergizes with doxorubicin. Overall, our data indicate that miR-34a expression is a strong predictor of outcome in EWS. Restoration of miR-34a activity may be useful to decrease malignancy and increase tumour sensitivity to current drugs, so sparing excessive long-term toxicity to EWS patients.     

抑制素与卵巢储备

1.抑制素的概念 抑制素(inhibin,INH)是由卵巢颗粒细胞分泌,分子量为31～32KDa的异二聚体糖蛋白激素,由α和β两种亚基通过二巯键连接而成,即INHA(αβA)和INHB(αβB).     

GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress

Cells regulate the rate of protein synthesis during conditions of cell stress to adapt to environmental changes. However, the molecular interactions between signaling pathways controlling translation and the cellular response to stress remain to be elucidated. Here, we show that the expression of growth arrest and DNA damage protein 34 (GADD34) is induced by energy depletion and that the expression of this protein protects cells from apoptotic cell death. During conditions of cell stress, GADD34 forms a stable complex with tuberous sclerosis complex (TSC) 1/2, causes TSC2 dephosphorylation, and inhibits signaling by mammalian target of the rapamycin (mTOR). These findings demonstrate that crosstalk between GADD34 and the mTOR signaling pathways contributes to the response of the protein synthetic machinery to environmental stress. GADD34 may find clinical potential as a target drug for the treatment of mTOR-associated diseases.     

G tolerance and the vasoconstrictor reserve

Purpose

Because leg arterial stiffness is higher in subjects with high G tolerance, we hypothesized that subjects with high G tolerance would have larger capacity for vasoconstriction.

Methods

Sixteen subjects, eight with high and eight with low G tolerance (H and L group, respectively), were exposed to a cold pressor test (CPT) in supine and upright posture. Heart rate (HR), mean arterial pressure (MAP) and cardiac output (CO) were measured, and total peripheral resistance (TPR) and stroke volume (SV) were calculated.

Results

In the supine position, CPT increased TPR more in the H group; 31 ± 18 % than in the L group; 11 ± 7 % (p < 0.05). The L group had larger increases in CO than the H group; 17 ± 16 vs. 3.4 ± 7 % (p = 0.06). In the upright position, the H group had a larger MAP response to CPT than the L group; 26 ± 14 vs. 14 ± 7 % (p = 0.06). The H group, but not the L group, had significant increases in TPR whereas the L group had significant increases in CO and SV.

Conclusions

In response to CPT, the high G tolerance group elevated MAP by increasing TPR, whereas the low G tolerance group showed a dependency on increased CO. The H group seemed to have a larger vasoconstrictor reserve. The results further suggest that vasoconstrictor reserve capacity could constitute the link between the recent finding that indicates a relationship between G tolerance and arterial distensibility in the legs.     

The effect of SAMe and betaine on Hepa 1-6, C34 and E47 liver cell survival in vitro

In recent years, methyl one-carbon metabolism has received a great deal of attention because the disruption of methyl balance in a variety of genetically modified mice is associated with the development of various forms of liver injury, namely fatty liver disease and hepatocellular carcinoma (HCC). In addition, patients with liver disease often have an abnormal expression of key genes involved in methionine metabolism as well as elevated serum levels of methionine and homocysteine (Hcy). S-adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte proliferation, necrosis and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of numerous forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and HCC. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also showed that it is effective in the treatment of patients with cholestatic liver diseases. We studied the survival of liver cells treated with SAMe and betaine using Hepa 1-6 and E47/C34 cell lines. We showed that exogenous SAMe decreased the number of Hepa 1-6 and E47/C34 cells, and increased the number of dead cells in vitro. Betaine had no significant effect on the number of surviving cells and the number of dead cells. The combination of both methyl donors significantly increased the survival of liver cells and reduced necrosis, compared to SAMe alone. This study showed the inhibition of the proliferation and increased necrosis in response to SAMe on liver cancer cell lines Hepa 1-6 and C34.     

认知操作、认知方式与神经质人格特质的关系

目的：考察认知操作、认知方式与神经质人格特质的关系。方法：对30名高神经质被试和30名低神经质被试进行实验性认知测试。结果：高低神经质被试在紧张、松弛条件下的认知操作测试总分方面差异不显著，但在紧张性-松弛性认知方式的评价分数上存在显著差异。高神经质被试更多地倾向于松弛型认知方式，低神经质被试更多地倾向于紧张型认知方式。结论：神经质人格与紧张、松弛条件下的认知操作测试总分无关，而与紧张性-松弛性认知方式存在相关关系。     

Vascular and metabolic reserve in Alzheimer's disease

Vascular and metabolic reserve were analyzed in probable Alzheimer's disease (AD) and vascular dementia (VaD). Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) were measured quantitatively with positron emission tomography (PET). Vascular reactivity (VR) was also calculated by comparing the CBF during 5% CO(2) inhalation with the CBF during normal breathing. Vascular transit time (VTT) that was calculated as a ratio of CBV/CBF and VR reflect vasodilating capacity of the small resistance vessels, whereas OEF designates metabolic (oxygen-extraction) reserve in threatening brain ischemia. Significant increase in OEF was seen in the parieto-temporal cortex and both VTT and VR were preserved in AD patients. By constrast, there was no significant increase in OEF whereas VTT was prolonged and VR was markedly depressed in VaD patients. The increase of OEF and preserved VTT and VR seen in AD patients indicate the possible participation of vascular factors in the pathogenesis of AD perhaps at the capillary level.     

Variability of ovarian reserve tests

Sir, The article by Kwee et al. (2004) on the intercycle variabilityof ovarian reserve tests contains important methodological pointsthat require further explanation and clarification before validconclusions can be drawn.

1. The authors mention that cycle day2 or 3 serum FSH values weredetermined as basal values duringclomiphene citrate challengetest (CCCT). It has been reportedthat there is considerablevariation in serum FSH levels between     

轻度认知损害患者的认知保存与缺损特点分析

目的:分析轻度认知损害(MCI)患者的认知保存与缺损的特征.方法:应用Mattis痴呆评定量表(DRS)中文版和简易智能状态检查(MMSE)评定正常老人88例、MCI患者23例和轻度阿尔茨海默病(AD)患者22例.结果:MCI组与正常老人组比较,"记忆"因子有显著减退,而"注意"、"起始/持续"、"结构"和"概念化"四个因子分差异有显著性.与轻度AD组相比,MCI组在总体智力、记忆功能、言语流畅性、执行功能方面的表现明显好于轻度AD患者.结论:上述结果初步反映了MCI的认知保持与缺损特征.