Dementia and Alzheimer's disease: A new direction. The 2010 Jay L. Foster Memorial Lecture

Kuller, Lewis H.; López, Oscar L.

doi:10.1016/j.jalz.2011.05.901

Cited by 26 publications

(20 citation statements)

References 142 publications

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“…A new Institute of Medicine report on cognitive aging has attempted to separate cognitive aging from AD and other specific causes of dementia, assuming that age-related cognitive decline is ‘normal’ and independent of specific neuropathology other than neurodegeneration [64]. The environmental and genetic determinants of brain aging may be different than the traditional risk factors evaluated in most epidemiological and clinical dementia studies [65]. …”

Section: Discussionmentioning

confidence: 99%

Risk of dementia and death in the long‐term follow‐up of the Pittsburgh Cardiovascular Health Study–Cognition Study

Kuller

López

Becker

et al. 2015

Alzheimer's & Dementia

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INTRODUCTION Increasing life expectancy has resulted in a larger population of older individuals at risk of dementia. METHODS The Cardiovascular Health Study–Cognition Study (CHS-CS) followed 532 participants from 1998–99 (mean age 79) to 2013 (mean age 93) for death and dementia. RESULTS Risk of death was determined by extent of coronary artery calcium, high-sensitivity cardiac troponin, and brain natriuretic peptide, and white matter grade. Significant predictors of dementia were age, apolipoprotein-E4, vocabulary raw score, hippocampal volume, ventricular size, cognitive performance, and number of blocks walked. By 2013, 160 of 532 were alive, including 19 cognitively normal. Those with normal cognition had higher grade education, better cognition test scores, greater hippocampal volume, faster gait speed, and number of blocks walked as compared to survivors who were demented. DISCUSSION Few survived free of dementia and disability. Prevention and delay of cognitive decline for this older population is an imperative.

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Section: Discussionmentioning

confidence: 99%

Risk of dementia and death in the long‐term follow‐up of the Pittsburgh Cardiovascular Health Study–Cognition Study

Kuller

López

Becker

et al. 2015

Alzheimer's & Dementia

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“…This refinement is based on evidence that Aβ 42 accumulation (at AD load levels) can be detected in both cognitively “normal” elderly and humanized mouse models with little learning and memory impairment (Snowdon, 2003; Zahs and Ashe, 2010). These observations have prompted a “re-imagining” of the amyloid hypothesis (Herrup, 2010; Kuller and Lopez, 2011; Nelson et al, 2011). Here, the amyloid deposition cycle, aggravated by chronic neuroinflammation, triggers a critical “change in state” (Herrup, 2010).…”

Section: Exploring a “Lipid-centric” View Of Synaptic Function And Dymentioning

confidence: 99%

Using neurolipidomics to identify phospholipid mediators of synaptic (dys)function in Alzheimer's Disease

Bennett¹,

Valenzuela²,

Xu³

et al. 2013

Front. Physiol.

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Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimer's Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion.

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“…The current situation has recently been summed up as supporting “three major hypotheses related to dementia: amyloid deposition and secondary synaptic loss, as a unique disease; vascular injury; and ‘aging’” (Kuller and Lopez, 2011). But how do we prevent “aging”?…”

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confidence: 99%

Age, Alzheimer's disease, and the big picture

Ganguli¹,

Rodríguez²

2011

International Psychogeriatrics

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The recently published revised National Institute on Aging/Alzheimer's Association clinical diagnostic criteria for Alzheimer's disease (AD) (Albert et al., 2011; Jack et al., 2011; McKhann et al., 2011; Sperling et al., 2011) have been hailed for incorporating a number of timely and important advances. They reflect new understanding that has been gained since the previous criteria were published in 1984 (McKhann et al., 1984). They include recognition of the state of mild cognitive impairment that is present before the threshold is crossed into dementia; they recognize the potential role of biomarkers in enhancing the specificity of diagnosis; they also address emerging work in the preclinical stage of AD that could help in understanding the sequence and stages of the core pathology before symptoms emerge. Among the previously listed diagnostic features that have disappeared was the requirement that onset of dementia occur before the age of 90 years. Meanwhile, the Neurocognitive Disorders Work Group for DSM-5 (the 5th edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 2010) is also doing away with the previous distinction between early-onset and late-onset dementia in AD, where an arbitrary division had been placed at age 65 (American Psychiatric Association, 2000). These changes are driven by the lack of biological data to support the age-based dichotomy, while recognizing the unique genetic characteristics of the relatively rare, autosomal dominantly inherited forms of AD which typically occur early. However, the disappearance of the age-based diagnostic dichotomy by no means implies that age is irrelevant to AD.

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Dementia and Alzheimer's disease: A new direction. The 2010 Jay L. Foster Memorial Lecture

Cited by 26 publications

References 142 publications

Risk of dementia and death in the long‐term follow‐up of the Pittsburgh Cardiovascular Health Study–Cognition Study

Risk of dementia and death in the long‐term follow‐up of the Pittsburgh Cardiovascular Health Study–Cognition Study

Using neurolipidomics to identify phospholipid mediators of synaptic (dys)function in Alzheimer's Disease

Age, Alzheimer's disease, and the big picture

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