Evaluation of the Neuroprotective Potential of N-Acetylcysteine for Prevention and Treatment of Cognitive Aging and Dementia.

Alzheimer's disease is a progressive neurodegenerative disease for which there is no cure and only a few treatments providing little relief. Increased oxidative stress that is associated with aging is strongly implicated in the pathogenesis and progression of Alzheimer's disease. Studies have shown that levels of the endogenous antioxidant glutathione decline at an early stage of Alzheimer's disease with decreased levels correlating with worse cognitive functions. N-acetylcysteine, a drug also widely available as a dietary supplement, is a precursor of L-cysteine, which in turn is a component of glutathione. Because cysteine availability is a limiting factor for glutathione synthesis, treatment with N-acetylcysteine may increase glutathione levels and thereby counter oxidative stress, promote redox -regulated cell signaling, and improve immune responses. In this review, we evaluate the existing literature and the potential of N-acetylcysteine in promoting cognitive health and alleviating cognitive decline associated with dementia. Discussion will also include possible mechanisms of action of N-acetylcysteine, its effects on aging biology, and safety of long-term use. Based on the available literature, a nutraceutical formulation containing N-acetylcysteine among other compounds has shown some pro-cognitive benefits in Alzheimer's patients and older adults, but the evidence for N-acetylcysteine alone is less robust. Although N-acetylcysteine crosses the blood-brain-barrier, low bioavailability is an obstacle. One promising avenue of research may be to explore derivatives of N-acetylcysteine such as N-acetylcysteine amide, which has been reported in preclinical studies to have higher permeability through cellular and mitochondrial membranes with increased central nervous system bioavailability compared to N-acetylcysteine.

Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer's disease.

Although nothing has been proven conclusively to protect against cognitive aging, Alzheimer's disease or related dementias, decades of research suggest that specific approaches including the consumption of coffee may be effective. While coffee and caffeine are known to enhance short-term memory and cognition, some limited research also suggests that long-term use may protect against cognitive decline or dementia. In vitro and pre-clinical animal models have identified plausible neuroprotective mechanisms of action of both caffeine and other bioactive components of coffee, though epidemiology has produced mixed results. Some studies suggest a protective association while others report no benefit. To our knowledge, no evidence has been gathered from randomized controlled trials. Although moderate consumption of caffeinated coffee is generally safe for healthy people, it may not be for everyone, since comorbidities and personal genetics influence potential benefits and risks. Future studies could include short-term clinical trials with biomarker outcomes to validate findings from pre-clinical models and improved epidemiological studies that incorporate more standardized methods of data collection and analysis. Given the enormous economic and emotional toll threatened by the current epidemic of Alzheimer's disease and other dementias, it is critically important to validate potential prevention strategies such as coffee and caffeine.

Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease.

An NIH State of the Science Conference panel concluded in 2010 that insufficient evidence is available to recommend the use of any primary prevention therapy for Alzheimer's disease or cognitive decline with age. Despite the insufficient evidence, candidate therapies with varying levels of evidence for safety and efficacy are taken by the public and discussed in the media. One example is the long-chain n-3 (omega-3) polyunsaturated fatty acids (n-3 LC-PUFA), DHA and EPA, found in some fish and dietary supplements. With this report, we seek to provide a practical overview and rating of the level and type of available evidence that n-3 LC-PUFA supplements are safe and protective against cognitive aging and Alzheimer's disease, with additional discussion of the evidence for effects on quality of life, vascular aging, and the rate of aging. We discuss available sources, dose, bioavailability, and variables that may impact the response to n-3 LC-PUFA treatment such as baseline n-3 LC-PUFA status, APOE ε4 genotype, depression, and background diet. Lastly, we list ongoing clinical trials and propose next research steps to validate these fatty acids for primary prevention of cognitive aging and dementia. Of particular relevance, epidemiology indicates a higher risk of cognitive decline in people in the lower quartile of n-3 LC-PUFA intake or blood levels but these populations have not been specifically targeted by RCTs.

Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting: Part II--Pharmacologic therapy. Alzheimer's Disease (AD) Managed Care Advisory Council.

The progressive loss of social and physical functioning associated with Alzheimer's disease (AD) results in extensive social and economic costs to society. The early diagnosis and treatment of AD may reduce cognitive and behavioral symptoms of this disease and may slow disease progression, thereby alleviating some of these social and economic costs. The Alzheimer's Disease Managed Care Advisory Council, a panel of experts from managed care, academic medicine, and the Los Angeles chapter of the Alzheimer's Association was convened to synthesize current evidence-based recommendations for AD diagnostic and treatment guidelines and to integrate these guidelines for use in MCOs. This paper presents conclusions from this panel and provides an algorithm for the treatment of AD specifically for managed care settings. When combined with other necessary efforts to educate providers, these guidelines should improve the cost-effectiveness and quality of care for individuals with dementia in managed care.

Binding of heparan sulfate glycosaminoglycan to beta-amyloid peptide: inhibition by potentially therapeutic polysulfated compounds.

Heparin sulfate proteoglycans are believed to play an important role in amyloidosis as pathologic chaperones. They bind to amyloidogenic proteins and may mediate the deposition and fibrillogenesis of amyloid at specific tissue sites. In the present study, we demonstrate that heparin sulfate glycosaminoglycan and proteoglycan both bind to the beta-amyloid peptide involved in Alzheimer's disease. The interaction of heparan sulfate proteoglycan and glycosaminoglycan can be inhibited by other sulfated compounds such as heparin, dextran sulfate and pentosan polysulfate. These polysaccharides which are currently used clinically, their derivatives or analogs may be effective as therapeutic agents to prevent or slow the progression of amyloidogenesis in Alzheimer's disease or other amyloidogenic disorders.

Immunogenicity of liposome-bound hyaluronate in mice. At least two different antigenic sites on hyaluronate are identified by mouse monoclonal antibodies.

Hyaluronate (HA) was previously demonstrated to be immunogenic in rabbits. The immunogenicity of HA in mice was studied. Hyaluronidase-digested streptococcal HA (IA1) covalently linked to liposomes (IA1-liposomes) were produced for immunization. Mice immunized with IA1-liposomes developed measurable serum antibodies to IA1, while mice immunized with IA1 in Freund's adjuvant did not. mAbs produced by two stable hybridomas (10G6 and 5F11) from mice immunized with IA1-liposomes produced IgG antibody reactive with HA in ELISA. 10G6 had a much higher avidity for liposome-bound IA1 than free IA1, while 5F11 did not, suggesting that the mode of presentation of IA1 is important in HA immunogenicity and antigenicity. Both mAbs recognized terminal HA immunodeterminants exposed by hyaluronidase treatment. Sonication had no effect on HA reactivity for either mAb. However, ascorbic acid treatment significantly reduced the antigenicity of HA for mAb 5F11, but not 10G6. Only 10G6 was inhibited by glucuronic acid. Electrostatic forces appear to play a role in the binding site of 5F11, but not 10G6. 5F11 crossreacts with heparan sulfate and phosphorylcholine, while 10G6 did not crossreact with any glycosaminoglycans or phosphorylated compounds tested. These results confirm that HA is immunogenic. They suggest that the mode of presentation of HA is important for the induction of the immune response, and in HA antigenicity. At least two different antigenic sites on HA were demonstrated. 10G6 recognizes a terminal HA antigenic site expressed on IA1-liposomes that contains glucuronic acid in its immunodominant site. 5F11 recognizes an HA antigenic site in which electrostatic forces appear to play a role, is sensitive to ascorbic acid treatment, and is crossreactive with heparan sulfate. The use of mAbs should facilitate immunologic studies of HA.