Transcriptome Analysis of Synaptoneurosomes Identifies Neuroplasticity Genes Overexpressed in Incipient Alzheimer's Disease

In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oAβ). To identify immediate molecular targets downstream of oAβ binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing discrimination of expression changes in synaptically localized genes. In IAD patients, global measures of cognition declined with increasing levels of dimeric Aβ (dAβ). These patients also showed increased expression of neuroplasticity related genes, many encoding 3′UTR consensus sequences that regulate translation in the synapse. An increase in mRNA encoding the GluR2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was paralleled by elevated expression of the corresponding protein in IAD. These results imply a functional impact on synaptic transmission as GluR2, if inserted, maintains the receptors in a low conductance state. Some overexpressed genes may induce early deficits in cognition and others compensatory mechanisms, providing targets for intervention to moderate the response to dAβ

A double-blind, randomized clinical trial of dietary supplementation on cognitive and immune functioning in healthy older adults

BACKGROUND: Declining cognitive function is relatively common and increasingly prevalent. Studies have shown that different nutrients (e.g., Ginkgo biloba and vitamin E) appear to be effective at improving memory and concentration, while less is known about their effect on immunity. METHODS: This study investigated the effect of Ginkgo Synergy® plus Choline (n = 33) and OPC Synergy® plus Catalyn® (n = 31) versus placebo (n = 33) in a 6-month, randomized, double-blind trial on cognitive and immune functioning among English-speaking, non-smoking, healthy older adults. The Stroop Color and Word Test, Trail Making Test A and B, Controlled Oral Word Association, Hopkins Verbal Learning, Mini-Mental State Exam, and Digit Symbol were administered at baseline and 3 and 6 months follow-up to assess cognitive functioning. Cytokines and growth factors were measured at baseline and 6 months to assess inflammation and immune functioning. Data were analyzed with linear mixed modeling. RESULTS: No serious adverse events were noted in this study. According to time on the Trail Making Test-B, the Ginkgo Synergy® plus Choline arm showed improvement from baseline to 3 months follow-up (mean difference = 24.2; SE = 6.4; 95% CI: 8.6, 39.7; p = 0.01). On the Controlled Oral Word Association Trial-S, the scores significantly increased for the Ginkgo Synergy® plus Choline arm from baseline to 6 months follow-up (mean difference = 2.1; SE = 0.8; 95% CI: 0.2, 3.9; p < 0.05) and for the OPC Synergy® plus Catalyn® arm from baseline to 3 months follow-up (mean difference = 2.1; SE = 0.8; 95% CI: 0.2, 4.0; p < 0.05). Epidermal growth factor significantly decreased from baseline to 6 months follow-up for the Ginkgo Synergy® plus Choline arm (mean difference = 120.7; SE = 28.4; 95% CI: 62.6, 178.8; p < 0.001). CONCLUSIONS: Our study showed isolated and modest effects of a Ginkgo biloba plus choline-based formula on cognitive and immune functioning among healthy older adults with no history of significant cognitive deficits. Our trial was registered with clinicaltrials.gov (ID: NCT01672359). This study was supported by a grant from Standard Process, Inc

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P = 0.002. Replication was sought in two additional cohorts (N = 670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence

The cross-cultural utility of foreign- and locally-derived normative data for three WHO-endorsed neuropsychological tests for South African adolescents

Interpretation of neuropsychological tests may be hampered by confounding sociodemographic factors and by using inappropriate normative data. We investigated these factors in three tests endorsed by the World Health Organization: the Grooved Pegboard Test (GPT), the Children's Color Trails Test (CCTT), and the WHO/UCLA version of the Auditory Verbal Learning Test (AVLT). In a sample of 12-15-year-old, Afrikaans- and English-speaking adolescents from the Cape Town region of South Africa, analyses of covariance (ANCOVAs) demonstrated that quality of education was the sociodemographic factor with the biggest influence on test performance, and that age also significantly influenced GPT and CCTT performance. Based on those findings, we provide appropriately stratified normative data for the age group in question. Comparisons between diagnostic interpretations made using foreign normative data versus those using the current local data demonstrate that it is imperative to use appropriately stratified normative data to guard against misinterpreting performance