Journal of Alzheimer's Disease - Volume 42, issue s4

Authors: Auchter, Allison | Williams, Justin | Barksdale, Bryan | Monfils, Marie H. | Gonzalez-Lima, Francisco

Article Type: Research Article

Abstract: Chronic cerebral hypoperfusion, a risk factor for mild cognitive impairment and Alzheimer's disease, affects mitochondrial respiration and memory consolidation. Therefore, drugs that improve mitochondrial function may be appropriate cognitive treatments for cerebral hypoperfusion. Methylene blue (MB) crosses the blood-brain barrier and at low doses serves as an electron cycler in the mitochondrial electron transport chain. Previous studies implicate MB in both memory enhancement and neuroprotection. We treated rats that underwent permanent bilateral carotid occlusion (2VO) or sham surgery with daily 4 mg/kg USP MB or saline for one month. Animals went through a battery of behavioral tests, including open field, …visual water maze, and odor-recognition tasks. 2VO rats showed worse performance in the visual water task without showing differences in general motor activity, visually guided swimming ability or odor recognition. Daily MB attenuated the deficits in visual learning and memory that resulted from cerebrovascular insufficiency. During training on three different discrimination problems in the visual water task, all animals were able to reach a criterion of 8/10 correct trials, but 2VO animals took longer to learn each problem and showed lower performance in a challenging memory probe. However, animals that received daily post-session MB performed significantly better than saline-treated subjects both during training and during the memory probe. This is the first study to demonstrate that MB attenuates learning and memory deficits caused by carotid occlusion. The results suggest that MB may be beneficial for conditions involving chronic cerebral hypoperfusion, such as mild cognitive impairment, vascular dementia, and Alzheimer's disease. Show more

Keywords: Carotid occlusion, cerebral hypoperfusion, cognitive impairment, memory enhancement, methylene blue

DOI: 10.3233/JAD-141527

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S525-S535, 2014

Authors: Grammas, Paula | Martinez, Joseph M.

Article Type: Review Article

Abstract: The Alzheimer's disease (AD) epidemic proceeds unabated. Estimates suggest 5.4 million Americans and 36 million people worldwide have AD. No single mechanism or pathologic mediator can account for AD progression. Currently no disease modifying therapies are available. There is a large literature documenting an association among cardiovascular risk factors (CVRFs), especially diabetes and hypoxia, with increased AD incidence. CVRFs directly impair vascular function and could mediate cerebrovascular dysfunction in AD. This is important as cerebrovascular dysfunction precedes cognitive decline and onset of neurodegenerative changes in AD and AD animal models. In this review we present evidence that thrombin may be …a heretofore unexplored target for AD therapy. This idea is based on the following observations. Thrombin is elevated in the brain and cerebral microvasculature in AD, is directly neurotoxic, and causes pro-inflammatory effects in endothelial cells, microglia, and astrocytes. Diabetes- and hypoxia-induced cerebrovascular effects are mediated by thrombin. Thrombin inhibitors block the effects of hypoxia on brain endothelial cells and reduce vascular inflammation in transgenic AD mice. Based on reports that reducing cerebrovascular expression of inflammatory proteins in AD mice is associated with improved cognition, we propose thrombin inhibitors could prove useful for improving cognition in AD patients. The next generation of AD therapeutics should not focus on single target drugs but rather employ a multi-component cocktail approach. We propose thrombin inhibitors be considered as potential contributors to the dementia therapy pharmacopeia. The urgent need for disease-modifying drugs in AD demands new thinking about disease pathogenesis and exploration of novel drug targets. Show more

Keywords: Alzheimer's disease, cardiovascular risk factors, cerebral microvasculature, cognitive decline, dabigatran, thrombin, thrombin inhibitors

DOI: 10.3233/JAD-141557

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S537-S544, 2014

Authors: Rafii, Michael S.

Article Type: Review Article

Abstract: In 2013, the Food and Drug Administration released draft guidance on drug development for early-stage Alzheimer's disease (AD). This guidance builds on the understanding that AD is a progressive disease with symptoms appearing long after neurodegeneration has begun. Preclinical AD relies on the conceptual distinction made between the presence of AD pathological processes and clinically observable symptoms. With the advent of new biomarkers that allow for presymptomatic detection of AD pathology, there now exists an opportunity to design and conduct clinical trials of putative disease-modifying drugs in the earliest stages of the disease when they are thought to have the …greatest chance of success. As such, there are four clinical trials planned or underway for the secondary prevention of AD. Show more

Keywords: Clinical trials, preclinical Alzheimer's disease

DOI: 10.3233/JAD-141482

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S545-S549, 2014

Authors: Gates, Nicola J. | Sachdev, Perminder

Article Type: Research Article

Abstract: There is much interest in early intervention for the prevention or postponement of dementia in Alzheimer's disease (AD). The results of drug trials in this regard have thus far been disappointing, and non-pharmacological interventions are receiving increased attention. One such intervention is complex cognitive activity. Evidence from epidemiological studies suggests that participation in stimulating mental activities is associated with lowered dementia risk. The introduction of novel and complex cognitive interventions to healthy adults and those with cognitive impairment may represent an efficacious treatment option to improve cognition, lower dementia incidence, and slow rate of decline. This review examines the evidence …for restorative cognitive training (CT) and addresses a number of clinically relevant issues regarding cognitive benefit and its transfer and persistence. Although the number of randomized controlled trials is limited, preliminary evidence suggests that CT may provide immediate and longer term cognitive benefits which generalize to non-trained domains and non-cognitive functions, with supervised small group multi-domain training providing greatest benefits. Possible neuroplastic mechanisms are discussed, and recommendations for further research and clinical implementation provided. Show more

Keywords: Alzheimer's disease, cognitive intervention, cognitive training, treatment

DOI: 10.3233/JAD-141302

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S551-S559, 2014

Authors: García-Barroso, Carolina | Ugarte, Ana | Martínez, Martín | Rico, Alberto J. | Lanciego, José Luis | Franco, Rafael | Oyarzabal, Julen | Cuadrado-Tejedor, Mar | García-Osta, Ana

Article Type: Review Article

Abstract: Understanding the cellular and molecular processes involved in learning and memory will help in the development of safe and effective cognitive enhancers. The cAMP response element-binding (CREB) may be a universal modulator of processes required for memory formation, and increasing the levels of second messengers like cAMP and cGMP could ultimately lead to CREB activation. Phosphodiesterase (PDE) inhibitors regulate signaling pathways by elevating cAMP and/or cGMP levels, and they have been demonstrated to improve learning and memory in a number of rodent models of impaired cognition. The aim of this review is to summarize the outstanding progress that has been …made in the application of PDE inhibitors for memory dysfunction. In addition, we have introduced some recent data we generated demonstrating that tadalafil could be considered as an optimal candidate for drug re-positioning and as a good candidate to enhance cognition. Show more

Keywords: Cerebrospinal fluid, cGMP, memory enhancement, phosphodiesterase, tadalafil

DOI: 10.3233/JAD-141341

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S561-S573, 2014

Authors: O'Caoimh, Rónán | Kehoe, Patrick Gavin | Molloy, D. William

Article Type: Review Article

Abstract: With the rising prevalence of cognitive impairment worldwide, clinicians are facing important challenges managing dementia, particularly Alzheimer's disease, the most prevalent dementia subtype. Given that current treatments mainly offer symptomatic improvement, without altering disease progression, the challenge now is to identify and integrate new therapeutic strategies. Hypertension is increasingly recognized as a modifiable risk factor for mild cognitive impairment (MCI), the precursor of dementia. The renin angiotensin aldosterone system (RAAS) is central to blood pressure regulation and medications targeting RAAS inhibition are associated with reduced rates of both cognitive and functional decline in those with MCI and dementia. Angiotensin converting …enzyme inhibitors and angiotensin receptor blockers are widely prescribed anti-hypertensives acting on the RAAS, and there is growing evidence that they act centrally, possibly exerting their effects independent of their blood pressure lowering properties. The relationship is complex however, and given the risks associated with hypotension particularly in older adults, treatment with these agents may not benefit all. Additionally, current evidence is limited to preclinical and observational studies such that there is now a pressing need to confirm preliminary studies with properly conducted randomized control trials. Here, we review some of the salient and complex aspects of these observations to date. Show more

Keywords: Alzheimer's disease, angiotensin converting enzyme inhibitors, dementia, hypertension, mild cognitive impairment, renin angiotensin aldosterone system

DOI: 10.3233/JAD-141284

Citation: Journal of Alzheimer's Disease, vol. 42, no. s4, pp. S575-S586, 2014