Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.

Impaired glucose uptake in the brain is one of the earliest presymptomatic manifestations of Alzheimer's disease (AD). The absence of symptoms for extended periods of time suggests that compensatory metabolic mechanisms can provide resilience. Here, we introduce the concept of a systemic 'bioenergetic capacity' as the innate ability to maintain energy homeostasis under pathological conditions, potentially serving as such a compensatory mechanism. We argue that fasting blood acylcarnitine profiles provide an approximate peripheral measure for this capacity that mirrors bioenergetic dysregulation in the brain. Using unsupervised subgroup identification, we show that fasting serum acylcarnitine profiles of participants from the AD Neuroimaging Initiative yields bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. To assess the potential clinical relevance of this finding, we examined factors that may offer diagnostic and therapeutic opportunities. First, we identified a genotype affecting the bioenergetic capacity which was linked to succinylcarnitine metabolism and significantly modulated the rate of future cognitive decline. Second, a potentially modifiable influence of beta-oxidation efficiency seemed to decelerate bioenergetic aging and disease progression. Our findings, which are supported by data from more than 9,000 individuals, suggest that interventions tailored to enhance energetic health and to slow bioenergetic aging could mitigate the risk of symptomatic AD, especially in individuals with specific mitochondrial genotypes.

Potential Neuroregenerative and Neuroprotective Effects of Uridine/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review.

In mild cognitive impairment (MCI) due to Alzheimer disease (AD), also known as prodromal AD, there is evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid [DHA]), which are key nutrients needed by the brain. Preclinical and clinical evidence shows the importance of nutrient bioavailability to support the development and maintenance of brain structure and function in MCI and AD. Availability of key nutrients is limited in MCI, creating a distinct nutritional need for uridine, choline, and DHA. Evidence suggests that metabolic derangements associated with ageing and disease-related pathology can affect the body's ability to generate and utilize nutrients. This is reflected in lower levels of nutrients measured in the plasma and brains of individuals with MCI and AD dementia, and progressive loss of cognitive performance. The uridine shortage cannot be corrected by normal diet, making uridine a conditionally essential nutrient in affected individuals. It is also challenging to correct the choline shortfall through diet alone, because brain uptake from the plasma significantly decreases with ageing. There is no strong evidence to support the use of single-agent supplements in the management of MCI due to AD. As uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, there is a compelling rationale to combine these nutrients. A multinutrient enriched with uridine, choline, and DHA developed to support brain function has been evaluated in randomized controlled trials covering a spectrum of dementia from MCI to moderate AD. A randomized controlled trial in subjects with prodromal AD showed that multinutrient intervention slowed brain atrophy and improved some measures of cognition. Based on the available clinical evidence, nutritional intervention should be considered as a part of the approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet, and consideration of evidence-based multinutrient supplements.

No calorie comfort: Viewing and drawing "comfort foods" similarly augment positive mood for those with depression.

Based on behavioral and neurobiological data, we tested the hypothesis that viewing/drawing visual images of comfort foods in the absence of eating will increase positive mood and that this effect is augmented for those with clinical symptoms of depression. A counterbalanced design was used for 60 participants with and without clinical symptoms in two variations: food image and food art. In each variation, participants viewed/drew foods high or low in fat/sugar; pre-post mood was recorded. Results show a consistent pattern: viewing/drawing comfort foods [food image (95% confidence interval): 2.72-4.85; food art (95% confidence interval): 2.65-4.62] and fruits [food image (95% confidence interval): 1.20-2.23; food art (95% confidence interval): 1.51-2.56] enhanced mood. For comfort foods, mood was augmented for those with clinical symptoms of depression [food image (95% confidence interval): 0.95-3.59; food art (95% confidence interval): 0.97-3.46]. Findings corroborate previous data and reveal a novel finding of augmented mood increases for those with clinical symptoms.

Change in Sense of Nondual Awareness and Spiritual Awakening in Response to a Multidimensional Well-Being Program.

OBJECTIVE: This study examined the effects of a comprehensive mind-body program on sense of nondual awareness and spiritual awakening. DESIGN AND INTERVENTION: The study compared the effects of participation in an intensive 6-day Ayurveda-based mind-body program that addressed physical, emotional, and spiritual domains as compared with a control condition. SETTING: Resort setting. SUBJECTS: Participants were 69 healthy women and men (mean age 53.9 years; range 32-86). OUTCOME MEASURE: The primary outcome was the Nondual Embodiment Thematic Inventory (NETI). RESULTS: A significant group by time interaction (p = 0.029) indicated that after the intervention, participants in the mind-body program showed a significant increase in NETI scores (p < 0.03), which was sustained 1 month later (p < 0.01). CONCLUSION: Findings suggest that an intensive program providing holistic instruction and experience in mind-body practices can lead to a significant and sustained shift in perception of self-awareness, one that is likely favorable to well-being.

Identification of Altered Metabolomic Profiles Following a Panchakarma-based Ayurvedic Intervention in Healthy Subjects: The Self-Directed Biological Transformation Initiative (SBTI).

The effects of integrative medicine practices such as meditation and Ayurveda on human physiology are not fully understood. The aim of this study was to identify altered metabolomic profiles following an Ayurveda-based intervention. In the experimental group, 65 healthy male and female subjects participated in a 6-day Panchakarma-based Ayurvedic intervention which included herbs, vegetarian diet, meditation, yoga, and massage. A set of 12 plasma phosphatidylcholines decreased (adjusted p < 0.01) post-intervention in the experimental (n = 65) compared to control group (n = 54) after Bonferroni correction for multiple testing; within these compounds, the phosphatidylcholine with the greatest decrease in abundance was PC ae C36:4 (delta = -0.34). Application of a 10% FDR revealed an additional 57 metabolites that were differentially abundant between groups. Pathway analysis suggests that the intervention results in changes in metabolites across many pathways such as phospholipid biosynthesis, choline metabolism, and lipoprotein metabolism. The observed plasma metabolomic alterations may reflect a Panchakarma-induced modulation of metabotypes. Panchakarma promoted statistically significant changes in plasma levels of phosphatidylcholines, sphingomyelins and others in just 6 days. Forthcoming studies that integrate metabolomics with genomic, microbiome and physiological parameters may facilitate a broader systems-level understanding and mechanistic insights into these integrative practices that are employed to promote health and well-being.

The Self-Directed Biological Transformation Initiative and Well-Being.

OBJECTIVE: To examine the effects of a comprehensive residential mind-body program on well-being. DESIGN: The Self-Directed Biological Transformation Initiative was a quasi-randomized trial comparing the effects of participation in a 6-day Ayurvedic system of medicine-based comprehensive residential program with a 6-day residential vacation at the same retreat location. SETTING: Retreat setting. PARTICIPANTS: 69 healthy women (n = 58) and men (n = 11) (mean age ± standard deviation, 53.6 ± 12 years). INTERVENTION: The Ayurvedic intervention addressed physical and emotional well-being through group meditation and yoga, massage, diet, adaptogenic herbs, lectures, and journaling. OUTCOME MEASURES: A battery of standardized questionnaires. RESULTS: Participants in the Ayurvedic program showed significant and sustained increases in ratings of spirituality (p < 0.01) and gratitude (p < 0.05) compared with the vacation group, which showed no change. The Ayurvedic participants also showed increased ratings for self-compassion (p < 0.01) as well as less anxiety at the 1-month follow-up (p < 0.05). CONCLUSIONS: Findings suggest that a short-term intensive program providing holistic instruction and experience in mind-body healing practices can lead to significant and sustained increases in perceived well-being and that relaxation alone is not enough to improve certain aspects of well-being.

Yoga on our minds: a systematic review of yoga for neuropsychiatric disorders.

BACKGROUND: The demand for clinically efficacious, safe, patient acceptable, and cost-effective forms of treatment for mental illness is growing. Several studies have demonstrated benefit from yoga in specific psychiatric symptoms and a general sense of well-being. OBJECTIVE: To systematically examine the evidence for efficacy of yoga in the treatment of selected major psychiatric disorders. METHODS: Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases, MEDLINE, EMBASE, and PsycINFO, were performed through April 2011 and an updated in June 2011 using the keywords yoga AND psychiatry OR depression OR anxiety OR schizophrenia OR cognition OR memory OR attention AND randomized controlled trial (RCT). Studies with yoga as the independent variable and one of the above mentioned terms as the dependent variable were included and exclusion criteria were applied. RESULTS: The search yielded a total of 124 trials, of which 16 met rigorous criteria for the final review. Grade B evidence supporting a potential acute benefit for yoga exists in depression (four RCTs), as an adjunct to pharmacotherapy in schizophrenia (three RCTs), in children with ADHD (two RCTs), and Grade C evidence in sleep complaints (three RCTs). RCTs in cognitive disorders and eating disorders yielded conflicting results. No studies looked at primary prevention, relapse prevention, or comparative effectiveness versus pharmacotherapy. CONCLUSION: There is emerging evidence from randomized trials to support popular beliefs about yoga for depression, sleep disorders, and as an augmentation therapy. Limitations of literature include inability to do double-blind studies, multiplicity of comparisons within small studies, and lack of replication. Biomarker and neuroimaging studies, those comparing yoga with standard pharmaco- and psychotherapies, and studies of long-term efficacy are needed to fully translate the promise of yoga for enhancing mental health.

Delivering happiness: translating positive psychology intervention research for treating major and minor depressive disorders.

Despite the availability of many treatment options, depressive disorders remain a global public health problem. Even in affluent nations, 70% of reported cases either do not receive the recommended level of treatment or do not get treated at all, and this percentage does not reflect cases of depression that go unreported due to lack of access to health care, stigma, or other reasons. In developing countries, the World Health Organization estimates that <10% receive proper depression care due to poverty, stigma, and lack of governmental mental health resources and providers. Current treatments do not work for everyone, and even people who achieve remission face a high risk of recurrence and residual disability. The development of low-cost effective interventions that can serve either as initial therapy for mild symptoms or as adjunctive therapy for partial responders to medication is an immense unmet need. Positive activity interventions (PAIs) teach individuals ways to increase their positive thinking, positive affect, and positive behaviors. The majority of such interventions, which have obtained medium-size effect sizes, have been conducted with nondepressed individuals, but two randomized controlled studies in patients with mild clinical depression have reported promising initial findings. In this article, the authors review the relevant literature on the effectiveness of various types of PAIs, draw on social psychology, affective neuroscience and psychophamacology research to propose neural models for how PAIs might relieve depression, and discuss the steps needed to translate the potential promise of PAIs as clinical treatments for individuals with major and minor depressive disorders.

Does meditation enhance cognition and brain plasticity?

Meditation practices have various health benefits including the possibility of preserving cognition and preventing dementia. While the mechanisms remain investigational, studies show that meditation may affect multiple pathways that could play a role in brain aging and mental fitness. For example, meditation may reduce stress-induced cortisol secretion and this could have neuroprotective effects potentially via elevating levels of brain derived neurotrophic factor (BDNF). Meditation may also potentially have beneficial effects on lipid profiles and lower oxidative stress, both of which could in turn reduce the risk for cerebrovascular disease and age-related neurodegeneration. Further, meditation may potentially strengthen neuronal circuits and enhance cognitive reserve capacity. These are the theoretical bases for how meditation might enhance longevity and optimal health. Evidence to support a neuroprotective effect comes from cognitive, electroencephalogram (EEG), and structural neuroimaging studies. In one cross-sectional study, meditation practitioners were found to have a lower age-related decline in thickness of specific cortical regions. However, the enthusiasm must be balanced by the inconsistency and preliminary nature of existing studies as well as the fact that meditation comprises a heterogeneous group of practices. Key future challenges include the isolation of a potential common element in the different meditation modalities, replication of existing findings in larger randomized trials, determining the correct "dose," studying whether findings from expert practitioners are generalizable to a wider population, and better control of the confounding genetic, dietary and lifestyle influences.

Pharmacovigilance in the 21st century: new systematic tools for an old problem.

The large number of adverse-event reports generated by marketed drugs and devices argues for the application of validated computerized algorithms to supplement traditional methods of detecting adverse-event signals. Difficulties in accurately estimating patient exposure and background rates for a given event in a specific population hinder risk estimation in spontaneous adverse-event databases. The United States Food and Drug Administration (FDA) is evaluating a Bayesian data mining system called Multi-item Gamma Poisson Shrinker (MGPS) to enhance the FDA's ability to monitor the safety of drugs, biologics, and vaccines after they have been approved for use. The MGPS computes adjusted higher-than-expected reporting relationships between drugs and adverse events across 35 years of data relative to internal background rates. The MGPS can also adjust for random noise by using a model derived from the data, and corrects for temporal trends and confounding related to age, sex, and other variables by stratifying over 900 categories. Signals can then be compared with or used in conjunction with other sources (e.g. clinical trials, general practice databases) to further study the adverse-event risk. The example of pancreatitis risk with atypical antipsychotics, valproic acid, and valproate is used to discuss the strengths and limitations of MGPS versus traditional methods. Validated data mining techniques offer great promise to enhance pharmacovigilance practices.

Current status of metals as therapeutic targets in Alzheimer's disease.

There is accumulating evidence that interactions between beta-amyloid and copper, iron, and zinc are associated with the pathophysiology of Alzheimer's disease (AD). A significant dyshomeostasis of copper, iron, and zinc has been detected, and the mismanagement of these metals induces beta-amyloid precipitation and neurotoxicity. Chelating agents offer a potential therapeutic solution to the neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper and zinc chelating agent clioquinol represents a potential therapeutic route that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the accumulation of neocortical beta-amyloid. A Phase II double-blind clinical trial of clioquinol with B12 supplementation will be published soon, and the results are promising. This article summarizes the role of transition metals in amyloidgenesis and reviews the potential promise of chelation therapy as a treatment for AD.

Non-cholinergic strategies for treating and preventing Alzheimer's disease.

The pathophysiology of Alzheimer's disease is complex and involves several different biochemical pathways. These include defective beta-amyloid (Abeta) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer's disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer's disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer's disease therapies are urgently needed. Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer's disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor-based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], gamma-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer's disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer's disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer's disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia. This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.

Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial.

CONTEXT: Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. OBJECTIVE: To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. DESIGN AND SETTING: Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. PARTICIPANTS: Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. INTERVENTIONS: Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. MAIN OUTCOME MEASURES: Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. RESULTS: On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. CONCLUSION: This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.