Dietary intervention and prevention of cognitive-related outcomes in healthy older adults without cognitive dysfunction

In the last decade, the association between diet and cognitive function/dementia has been largely investigated in observational studies, while there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we reviewed RCTs published in the last three years (2014-2016) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged over 60 years using different levels of investigation (i.e., dietary pattern changes/ medical food/nutraceutical supplementation/multidomain approach and dietary macro-and micronutrient approaches). From the included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. Moreover, there was high evidence that protein supplementation improved specific cognitive domains. For fatty acid supplementation, mainly long-chain polyunsaturated fatty acids, there was emerging evidence suggesting an impact of this approach in improving specific cognitive domains, MRI findings, and/or cognitive-related biomarkers also in selected subgroups of older subjects although some results were conflicting. Moreover, there was convincing evidence of an impact of non-flavonoid polyphenol and flavonoid supplementations in improving specific cognitive domains and/or MRI findings. Finally, there was only low evidence suggesting efficacy of intervention with homocysteine-related vitamins in improving cognitive functions, dementia incidence, or cognitive-related biomarkers in cognitively healthy older subjects

Dietary patterns, foods, and food groups : relation to late-life cognitive disorders

The limited efficacy of disease-modifying therapeutic strategies for mild cognitive impairment (MCI) and Alzheimer\u2019s dementia (AD) underscores the need for preventive measures to reduce the burden of late-life cognitive impairment. The aim of the present review article was to investigate the relationship among dietary patterns, foods, and food groups and late-life cognitive disorders considering the results of observational studies published in the last three years (2014-2016). In the last decade, the association between diet and cognitive function or dementia has been largely investigated. However, more recently, the National Institute on Aging-Alzheimer\u2019s Association guidelines for AD and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. Several studies focused on the role of the dietary patterns on late-life cognition, with accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline, although the Mediterranean diet (MeDi) combines several foods, micronutrients, and macronutrients already separately proposed as potential protective factors against dementia and MCI. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction in AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with added sugars and trans fatty acids, nutrients also increasing the cardiovascular risk. This would suggest a genesis for the same damage for aging brain

Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Nutritional interventions in patients with Alzheimer’s disease and other late-life cognitive disorders

Given the impact of nutrition on neuroprotection largely investigated in observational studies, in the present article, we reviewed evidence from randomized clinical trials (RCTs) published in the last three years (2014-2016) exploring nutritional intervention efficacy in slowing cognitive impairment progression and achieving cognitive-related outcomes in patients aged 60 years and older with mild cognitive impairment (MCI), preclinical Alzheimer\u2019s disease (AD), prodromal AD, AD, unspecified dementia, and vascular dementia using different levels of investigation (i.e., medical food/nutraceutical supplementation/multidomain approach and dietary food/macro-and micronutrient approaches). From the reviewed RCTs, there was emerging evidence that nutritional intervention through medical food/nutraceutical supplementation (Fortasyn Connect\uae and another similar nutraceutical formulation) and multidomain approach improved magnetic resonance imaging findings and other cognitive-related biomarkers, but without clear effect on cognition in mild AD and MCI. Moreover, there was some evidence of a positive effect of antioxidant-rich foods (nuts) in improving specific cognitive domains and cognitive-related outcomes in MCI and mild-to-moderate dementia, but only in small samples. There was also convincing evidence for fatty acid supplementation, mainly n-3 polyunsaturated fatty acids (PUFAs), in improving specific cognitive domains and/or cognitive-related biomarkers in MCI and AD. Furthermore, antioxidant vitamin and trace element supplementations improved only cognitive-related outcomes and biomarkers, without effect on cognitive function in AD and MCI patients. Finally, high-dose B vitamin supplementation in AD and MCI patients improved cognitive outcomes but only in the subjects with a high baseline plasma n-3 PUFA, while folic acid supplementation had positive impact on specific cognitive domains

Neurocognitive and Neuroimaging Predictors of Clinical Outcome in Bipolar Disorder

Historically, bipolar disorder has been conceptualized as a disease involving episodic rather than chronic dysfunction. However, increasing evidence indicates that bipolar disorder is associated with substantial inter-episode psychosocial and vocational impairment. Here we review the contributions of neurocognitive deficits and structural and functional neuroanatomic alterations to the observed functional impairments. In particular, compelling evidence now suggests that neurocognitive impairments, particularly in the areas of attention, processing speed, and memory, are associated with functional outcome. Although investigation of the neural correlates of functional disability in bipolar disorder is only in its nascent stages, preliminary evidence suggests that white matter abnormalities may be predictive of poor outcome. A better understanding of the relationship between neurocognitive and neuroimaging assays and functional outcome has the potential to improve current treatment options and provide targets for new treatment strategies in bipolar disorder

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.Peer reviewe

Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive (“discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms—early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways—that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness

Evaluation of the performance of Dutch Lipid Clinic Network score in an Italian FH population: The LIPIGEN study

Background and aims: Familial hypercholesterolemia (FH) is an inherited disorder characterized by high levels of blood cholesterol from birth and premature coronary heart disease. Thus, the identification of FH patients is crucial to prevent or delay the onset of cardiovascular events, and the availability of a tool helping with the diagnosis in the setting of general medicine is essential to improve FH patient identification.Methods: This study evaluated the performance of the Dutch Lipid Clinic Network (DLCN) score in FH patients enrolled in the LIPIGEN study, an Italian integrated network aimed at improving the identification of patients with genetic dyslipidaemias, including FH.Results: The DLCN score was applied on a sample of 1377 adults (mean age 42.9 +/- 14.2 years) with genetic diagnosis of FH, resulting in 28.5% of the sample classified as probable FH and 37.9% as classified definite FH. Among these subjects, 43.4% had at least one missing data out of 8, and about 10.0% had 4 missing data or more. When analyzed based on the type of missing data, a higher percentage of subjects with at least 1 missing data in the clinical history or physical examination was classified as possible FH (DLCN score 3-5). We also found that using real or estimated pre-treatment LDL-C levels may significantly modify the DLCN score.Conclusions: Although the DLCN score is a useful tool for physicians in the diagnosis of FH, it may be limited by the complexity to retrieve all the essential information, suggesting a crucial role of the clinical judgement in the identification of FH subjects

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function : a report from the COGENT consortium

CORRIGENDUM Molecular Psychiatry (2017) 22, 1651–1652 http://www.nature.com/articles/mp2017197.pdfThe complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (similar to 8M single-nucleotide polymorphisms (SNP) with minor allele frequency >= 1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (PPeer reviewe