Executive Dysfunction in MCI: Subtype or Early Symptom

Mild cognitive impairment (MCI) may take several forms, and amnestic MCI (aMCI) has been recognized as an early stage of Alzheimer's Disease (AD). Impairment in executive functions including attention (eMCI) may be indicative of several neurodegenerative conditions. Executive impairment is frequently found in aMCI, it is significant for prognosis, and patients with eMCI may go on to develop AD. Recent studies have found changes in white matter integrity in patients with eMCI to be more sensitive than measures of cortical atrophy. Studies of genetic high-risk groups using sensitive cognitive neuroscience paradigms indicate that changes in executive function may be a cognitive marker useful for tracking development in an AD pathophysiological process

Hemispheric asymmetry in visual discrimination and memory: ERP evidence for the spatial frequency hypothesis

Event related potentials (ERPs) were recorded during delayed discrimination of simple spatial frequency gratings in the high and low frequency bands. Analyses of the waveforms N170, P220, N310, P400, and slow wave (SW) indicated significant and regionally specific interaction of spatial frequency and hemisphere for N170 amplitude. This interaction was independent of memory conditions, and appeared to be in the opposite direction of what is predicted by the spatial frequency model of hemispheric asymmetry. Additional interactions between spatial frequency and hemisphere were observed for N310 in the encoding process (reference stimulus) and for SW in the retrieval process (test stimulus). The general hypothesis of an interaction of spatial frequency and hemisphere in visual cognition is supported, but the findings indicate caution in interpreting an increase in physiological measures as an indication of more efficient brain processing. Moreover, several stages of information processing may contribute to the asymmetry observed in behavioral studies, and hemispheric balance may change dynamically during the time course of processing

Brain regions involved in spatial frequency discrimination: evidence from fMRI

The cortical areas underlying successive spatial-frequency discrimination were explored using functional magnetic resonance imaging (fMRI). In a steady-state, block-design paradigm, 12 subjects viewed a single fixation cross during a rest period, followed by an activation period consisting of the presentation of horizontal (distractors) and vertical (targets) sinewave gratings. Two tasks were performed: in the control task, subjects pressed a button after the second vertical grating was presented within each trial; in the discrimination task, subjects decided which target grating had the higher spatial frequency. Post-processing consisted of off-line image registration to correct for head motion, spatial and temporal smoothing, and cross-correlation between each voxel time course and a phase-shifted stimulus time profile. The results indicate that striate, extrastriate, parietal, and prefrontal areas show significant BOLD (blood oxygen level dependent) effects during both discrimination and control tasks, with consistently higher activity levels in the discrimination task

Electrophysiological localization of brain regions involved in perceptual memory

Event-related potentials (ERP) were recorded during perceptual discrimination and short-term memory, varying the interstimulus interval (1–10 s) in delayed spatial frequency discrimination. Accuracy of discrimination remained unimpaired across this time interval, but choice reaction times increased. A brain source localization (BESA) model showed that the activity of the parietal and right temporal sources increased with long retention intervals in a sequential activation pattern where a long-latency component of the parietal source specific to the memory condition was observed, the latency of which matched a memory-related increase in choice reaction times in the cognitive task. It is suggested that the temporal sources are involved in encoding and storage of visual information, and the parietal source is involved in memory retrieval

Neurogenetic Effects on Cognition in Aging Brains: A Window of Opportunity for Intervention?

Knowledge of genetic influences on cognitive aging can constrain and guide interventions aimed at limiting age-related cognitive decline in older adults. Progress in understanding the neural basis of cognitive aging also requires a better understanding of the neurogenetics of cognition. This selective review article describes studies aimed at deriving specific neurogenetic information from three parallel and interrelated phenotype-based approaches: psychometric constructs, cognitive neuroscience-based processing measures, and brain imaging morphometric data. Developments in newer genetic analysis tools, including genome wide association, are also described. In particular, we focus on models for establishing genotype–phenotype associations within an explanatory framework linking molecular, brain, and cognitive levels of analysis. Such multiple-phenotype approaches indicate that individual variation in genes central to maintaining synaptic integrity, neurotransmitter function, and synaptic plasticity are important in affecting age-related changes in brain structure and cognition. Investigating phenotypes at multiple levels is recommended as a means to advance understanding of the neural impact of genetic variants relevant to cognitive aging. Further knowledge regarding the mechanisms of interaction between genetic and preventative procedures will in turn help in understanding the ameliorative effect of various experiential and lifestyle factors on age-related cognitive decline

Variants in Doublecortin- and Calmodulin Kinase Like 1, a Gene Up-Regulated by BDNF, Are Associated with Memory and General Cognitive Abilities

Human memory and general cognitive abilities are complex functions of high heritability and wide variability in the population. The brain-derived neurotrophic factor (BDNF) plays an important role in mammalian memory formation.Based on the identification of genes markedly up-regulated during BDNF-induced synaptic consolidation in the hippocampus, we selected genetic variants that were tested in three independent samples, from Norway and Scotland, of adult individuals examined for cognitive abilities. In all samples, we show that markers in the doublecortin- and calmodulin kinase like 1 (DCLK1) gene, are significantly associated with general cognition (IQ scores) and verbal memory function, resisting multiple testing. DCLK1 is a complex gene with multiple transcripts which vary in expression and function. We show that the short variants are all up-regulated after BDNF treatment in the rat hippocampus, and that they are expressed in the adult human brain (mostly in cortices and hippocampus). We demonstrate that several of the associated variants are located in potential alternative promoter- and cis-regulatory elements of the gene and that they affect BDNF-mediated expression of short DCLK1 transcripts in a reporter system.These data present DCLK1 as a functionally pertinent gene involved in human memory and cognitive functions

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders. Methods: Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium. Results: The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope. Conclusions: Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders

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

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