Aging of the brain, entropy, and Alzheimer disease

Department of Neurology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Neurology (Impact Factor: 8.29). 11/2006; 67(8):1340-52. DOI: 10.1212/01.wnl.0000240127.89601.83
Source: PubMed


Sporadic Alzheimer disease (AD) is related to advancing age far more than to any other risk factor and ultimately affects almost half of the population over age 85. Despite its remarkable prevalence among the elderly, it has been regarded as a specific disease, distinct from "normal aging." This view is supported in large part by clinical and pathologic similarities to early-onset, dominantly inherited familial AD, where genetic mutations related to beta-amyloid have been identified. There is much evidence that sporadic AD overlaps with normal aging in many clinical and pathologic features. Some of the many molecular age-related changes (ARCs) affecting the brain, both intrinsic (programmed) and extrinsic (stochastic), are reviewed, with discussion of the effects they have singly and collectively on neuronal viability and vulnerability. The effect of ARCs on the brain is seen as the biologic manifestation of increasing entropy, an approach that helps to explain the progressive decline of neural and cognitive function over time; the ability of multiple, varied ARCs to summate as individuals age; the transitional relationship between normal aging, mild cognitive impairment, and AD; and the apparent differences between normal aging and AD. Increasing entropy, manifest through a complex network of interacting ARCs, is seen as the fundamental driving cause of neural and cognitive decline in the elderly, as well as the overriding etiologic principle in further transition to sporadic AD. Research on sporadic AD has largely focused on finding a single causal metabolic disorder or genetic mutation. Multiple ARCs contribute to declining function and increased frailty in the aging brain, however, and to the catastrophic disintegration of sporadic AD. Effective prevention or treatment will depend on recognizing the contributions of a multiplicity of ARCs to AD and reducing the burden of as many as possible. The role of amyloid is seen as one element in the larger network of senescent changes involving the aging brain.

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Available from: David A Drachman, Jun 03, 2015
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    • "So far, the etiology of AD remains unknown. However, many factors have been involved and also some hypotheses have been proposed trying to explain the beginning and progression of the neurodegenerative process observed in this disorder [3]. One of these hypotheses is the " amyloid hypothesis, " which supports the idea that beta-amyloid peptide (Aí µí»½) plays a very important role in the origin and progression of the nervous tissue damage seen in these patients [4]. "

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    • "Healthy aging is associated with mild and gradual declines in cognition functions, with the greatest aging-related changes involving memory , processing speed, and visuospatial skills (Salthouse, 2010). Such changes often occur in parallel with age-related alterations in brain structure, characterized by cortical atrophy and white matter abnormalities (Drachman, 2006; Kramer et al., 2007). Paradoxically, fMRI studies have consistently found increased regional brain activity in healthy elders relative to their younger counterparts during the performance of a cognitive task. "
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    ABSTRACT: Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer's disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65-85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy. Copyright © 2015 Elsevier Inc. All rights reserved.
    NeuroImage 02/2015; 111. DOI:10.1016/j.neuroimage.2015.02.011 · 6.36 Impact Factor
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    • "Till today several disappointing clinical trials have disqualified targets that were believed to be in the main pathway of disease, such as amyloid-beta (Abeta), tau, beta-side amyloid precursor protein cleaving enzyme (BACE) etc. As a result researchers have to face a relative shortage of relevant targets (Armstrong, 2011; Braak and Braak, 1991; Drachman, 2006; Fjell and Walhovd, 2012; Herrup, 2010; Pimplikar, 2009; Pimplikar et al., 2010; Reitz, 2012). These negative clinical trials draw attention to the inefficient translational power of current animal models and call for the improvement of predictive value (Sarter et al., 2009). "
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    ABSTRACT: There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials. © The Author(s) 2015.
    Journal of Psychopharmacology 01/2015; 29(4). DOI:10.1177/0269881114565652 · 3.59 Impact Factor
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