دانلود رایگان مقاله انگلیسی رابطه استرس و بیماری آلزایمر - الزویر 2018

ABSTRACT

Stress is critically involved in the development and progression of disease. From the stress of undergoing treatments to facing your own mortality, the physiological processes that stress drives have a serious detrimental effect on the ability to heal, cope and maintain a positive quality of life. This is becoming increasingly clear in the case of neurodegenerative diseases. Neurodegenerative diseases involve the devastating loss of cognitive and motor function which is stressful in itself, but can also disrupt neural circuits that mediate stress responses. Disrupting these circuits produces aberrant emotional and aggressive behavior that causes long-term care to be especially difficult. In addition, added stress drives progression of the disease and can exacerbate symptoms. In this review, I describe how neural and endocrine pathways activated by stress interact with ongoing neurodegenerative disease from both a clinical and experimental perspective.

8. Stress in AD treatment

Given the increasing evidence that stress can have a deleterious effect on AD and other neurodegenerative disease progression, the question remains whether this information will aid in the treatment of AD. This can be looked at in a number of ways. Stress clearly exacerbates AD pathogenesis in AD model animals; lifestyle changes that reduce stress should be endorsed as protective against dementias, although this has not yet been proven in humans. In addition, pharmacologic therapies that selectively lower stress hormone levels (e.g. CRFR1 antagonists) should be tested for efficacy in slowing AD progression in humans. Treatment with the CRFR1 antagonist R121919 has been shown to decrease amyloid pathology and improve synaptic and cognitive function in AD model mice; however, this compound has not yet been tested in dementia patients (Zhang et al., 2015, 2016). Pharmacologic strategies that inhibit other aspects of the HPA axis have been tested in AD patients, with limited success. Glucocorticoid receptor antagonist treatment (RU486), which has been shown to decrease AD pathogenesis in mouse models (Baglietto-Vargas et al., 2015; Lante et al., 2015), led to a moderate improvement in cognitive scores in a small clinical trial (Belanoff et al., 2002; Pomara et al., 2002). Inhibition of the production of corticosteroids with an 11-β-hydroxysteroid dehydrogenase (11-β-HSD) inhibitor did not have an impact on cognitive scores of dementia patients in a randomized clinical trial (Marek et al., 2014). Increasing GR signaling by administration of the corticosteroid, prednisone, had no effect on cognitive performance in dementia patients (Aisen et al., 2000). Differences between laboratory (mouse) and clinical (human) experimental results may be due to different dosage or timing of drug delivery, or because most preliminary trials are conducted in patients that already experience substantial loss in cognitive ability, perhaps too late in disease progression to improve cognition by addressing aberrant stress hormone signaling.