Numerous studies show that happy individuals are successful across multiple life domains, including marriage, friendship, income, work performance, and health. The authors suggest a conceptual model to account for these findings, arguing that the happiness-success link exists not only because success makes people happy, but also because positive affect engenders success. Three classes of evidence--crosssectional, longitudinal, and experimental--are documented to test their model. Relevant studies are described and their effect sizes combined meta-analytically. The results reveal that happiness is associated with and precedes numerous successful outcomes, as well as behaviors paralleling success. Furthermore, the evidence suggests that positive affect--the hallmark of well-being--may be the cause of many of the desirable characteristics, resources, and successes correlated with happiness. Limitations, empirical issues, and important future research questions are discussed.

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The Benefits of Frequent Positive Affect: Does Happiness Lead to Success?

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

This report describes the first human study of a novel amyloid-imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound-B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94-fold, p = 0.0001). Large increases also were observed in parietal (1.71-fold, p = 0.0002), temporal (1.52-fold, p = 0.002), and occipital (1.54-fold, p = 0.002) cortex and the striatum (1.76-fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 +/- 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F-fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = -0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68880-6.pdf

Mild cognitive impairment

The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

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Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria

Objective. —To determine the relationship of brain infarction to the clinical expression of Alzheimer disease (AD). Design. —Cognitive function and the prevalence of dementia were determined for participants in the Nun Study who later died. At autopsy, lacunar and larger brain infarcts were identified, and senile plaques and neurofibrillary tangles in the neocortex were quantitated. Participants with abundant senile plaques and some neurofibrillary tangles in the neocortex were classified as having met the neuropathologic criteria for AD. Setting. —Convents in the Midwestern, Eastern, and Southern United States. Participants. —A total of 102 college-educated women aged 76 to 100 years. Main Outcome Measures. —Cognitive function assessed by standard tests and dementia and AD assessed by clinical and neuropathologic criteria. Results. —Among 61 participants who met the neuropathologic criteria for AD, those with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. Participants with lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without infarcts (the odds ratio [OR] for dementia was 20.7,95% confidence interval [95% CI], 1.5-288.0). Fewer neuropathologic lesions of AD appeared to result in dementia in those with lacunar infarcts in the basal ganglia, thalamus, or deep white matter than in those without infarcts. In contrast, among 41 participants who did not meet the neuropathologic criteria for AD, brain infarcts were only weakly associated with poor cognitive function and dementia. Among all 102 participants, atherosclerosis of the circle of Willis was strongly associated with lacunar and large brain infarcts. Conclusion. —These findings suggest that cerebrovascular disease may play an important role in determining the presence and severity of the clinical symptoms of AD.

Brain Infarction and the Clinical Expression of Alzheimer Disease: The Nun Study

Handwritten autobiographies from 180 Catholic nuns, composed when participants were a mean age of 22 years, were scored for emotional content and related to survival during ages 75 to 95. A strong inverse association was found between positive emotional content in these writings and risk of mortality in late life (p < .001). As the quartile ranking of positive emotion in early life increased, there was a stepwise decrease in risk of mortality resulting in a 2.5-fold difference between the lowest and highest quartiles. Positive emotional content in early-life autobiographies was strongly associated with longevity 6 decades later. Underlying mechanisms of balanced emotional states are discussed. Longevity may be related to a variety of factors including heredity, gender, socioeconomic status, nutrition, social support, medical care, and personality and behavioral characteristics (Robine, Vaupel, Jeune, & Allard, 1997). These factors might operate throughout life or at particular life stages. Recent findings from the Nun Study, a longitudinal study of older Catholic sisters, indicated that linguistic ability in early life is associated with survival in late life (Snowdon, Greiner, Kemper, Nanayakkara, & Mortimer, 1999). In that study, the idea density (proposition, information, and content) of autobiographies written at a mean age of 22 years was strongly related to survival and longevity 6 decades later. Because

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Positive emotions in early life and longevity: Findings from the nun study.

Objective. —To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life. Design. —Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically. Setting. —Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area. Participants. —Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age. Main Outcome Measures. —Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease. Results. —Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density. Conclusions. —Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life. (JAMA. 1996;275:528-532)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=jama&articleId=396775&pdfFileName=jama_275_7_029.pdf

Linguistic Ability in Early Life and Cognitive Function and Alzheimer's Disease in Late Life: Findings From the Nun Study

In Reply. —The analyses of Drs Mirra and Gearing indicate that brain infarcts are not associated with NFTs in the neocortex. Our analyses also indicated that brain infarcts were not associated with the number of NFTs, senile plaques, or neuritic plaques in the neocortex, suggesting that AD lesions and brain infarcts were likely to have occured independently of each other. While AD and brain infarction may represent separate disease processes, their combination may nonetheless increase the likelihood that dementia will occur. Among the participants in our study who met our neuropathologic criteria for AD (ie, abundant senile plaques and some NFTs in the neocortex), those with 1 or 2 lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without brain infarcts. The prevalence of dementia was 93% for those with such subcortical lacunar infarcts and 57% in those without infarcts.

https://jamanetwork.com/journals/jama/articlepdf/417387/jama_278_2_024.pdf

Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply

The development of interventions designed to delay the onset of dementia highlights the need to determine the neuropathologic characteristics of individuals whose cognitive function ranges from intact to demented, including those with mild cognitive impairments. We used the Braak method of staging Alzheimer's disease pathology in 130 women ages 76-102 years who were participants in the Nun Study, a longitudinal study of aging and Alzheimer's disease. All participants had complete autopsy data and were free from neuropathologic conditions other than Alzheimer's disease lesions that could affect cognitive function. Findings showed a strong relationship between Braak stage and cognitive state. The presence of memory impairment was associated with more severe Alzheimer's disease pathology and higher incidence of conversion to dementia in the groups classified as having mild or global cognitive impairments. In addition to Braak stage, atrophy of the neocortex was significantly related to the presence of dementia. Our data indicate that Alzheimer's neurofibrillary pathology is one of the neuropathologic substrates of mild cognitive impairments. Additional studies are needed to help explain the variability in neuropathologic findings seen in individuals whose cognitive performance falls between intact function and dementia.

David A. Snowdon

Papers

Brain Infarction and the Clinical Expression of Alzheimer Disease: The Nun Study

Positive emotions in early life and longevity: Findings from the nun study.

Linguistic Ability in Early Life and Cognitive Function and Alzheimer's Disease in Late Life: Findings From the Nun Study

Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply

Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study