Efficacy difference of antipsychotics in Alzheimer's disease and schizophrenia: explained with network efficiency and pathway analysis methods.

Approximately 50% of Alzheimer's disease (AD) patients will develop psychotic symptoms and these patients will experience severe rapid cognitive decline compared with those without psychosis (AD-P). Currently, no medication has been approved by the Food and Drug Administration for AD with psychosis (AD+P) specifically, although atypical antipsychotics are widely used in clinical practice. These drugs have demonstrated modest efficacy in managing psychosis in individuals with AD, with an increased frequency of adverse events, including excess mortality. We compared the differences between the genetic variations/genes associated with AD+P and schizophrenia from existing Genome-Wide Association Study and differentially expressed genes (DEGs). We also constructed disease-specific protein-protein interaction networks for AD+P and schizophrenia. Network efficiency was then calculated to characterize the topological structures of these two networks. The efficiency of antipsychotics in these two networks was calculated. A weight adjustment based on binding affinity to drug targets was later applied to refine our results, and 2013 and 2123 genes were identified as related to AD+P and schizophrenia, respectively, with only 115 genes shared. Antipsychotics showed a significantly lower efficiency in the AD+P network than in the schizophrenia network (P < 0.001) indicating that antipsychotics may have less impact in AD+P than in schizophrenia. AD+P may be caused by mechanisms distinct from those in schizophrenia which result in a decreased efficacy of antipsychotics in AD+P. In addition, the network analysis methods provided quantitative explanations of the lower efficacy of antipsychotics in AD+P.

A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development.

Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.

Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease.

BACKGROUND: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION: Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. HIGHLIGHTS: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE-𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families.

Terminal type-specific cannabinoid CB1 receptor alterations in patients with schizophrenia: A pilot study.

BACKGROUND: Individuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types - a factor previously unaccounted for when examining CB1R changes in schizophrenia - may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia. METHODS: Using co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals (nine male pairs and one female pair) diagnosed with schizophrenia and non-psychiatric comparisons. RESULTS: Significantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples. CONCLUSION: Given CB1R's role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study: A resource for genetic discovery.

INTRODUCTION: The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). METHODS: Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. RESULTS: APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. DISCUSSION: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.

Auditory dysfunction in schizophrenia: integrating clinical and basic features.

Schizophrenia is a complex neuropsychiatric disorder that is associated with persistent psychosocial disability in affected individuals. Although studies of schizophrenia have traditionally focused on deficits in higher-order processes such as working memory and executive function, there is an increasing realization that, in this disorder, deficits can be found throughout the cortex and are manifest even at the level of early sensory processing. These deficits are highly amenable to translational investigation and represent potential novel targets for clinical intervention. Deficits, moreover, have been linked to specific structural abnormalities in post-mortem auditory cortex tissue from individuals with schizophrenia, providing unique insights into underlying pathophysiological mechanisms.

Animal Models of Psychosis in Alzheimer Disease.

Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes.

Psychosis in Alzheimer's Disease.

PURPOSE OF REVIEW: To review the incidence, treatment and genetics of psychosis in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). RECENT FINDINGS: Psychosis in Alzheimer's disease (AD) has an incidence of ~ 10% per year. There is limited evidence regarding psychological interventions. Pharmacological management has focused on atypical antipsychotics, balancing modest benefits with evidence of long-term harms. The 5HT2A inverse agonist pimavanserin appears to confer benefit in PD psychosis with initial evidence of benefit in AD. Cholinesterase inhibitors give modest benefits in DLB psychosis. The utility of muscarinic agonists, lithium, glutamatergic and noradrenergic modulators needs further study. Recent work has confirmed the importance of psychosis in MCI as well as AD. The lack of evidence regarding psychological therapies is an urgent knowledge gap, but there is encouraging evidence for emerging pharmacological treatments. Genetics will provide an opportunity for precision medicine and new treatment targets.

The Performance of Gene Expression Signature-Guided Drug-Disease Association in Different Categories of Drugs and Diseases.

A gene expression signature (GES) is a group of genes that shows a unique expression profile as a result of perturbations by drugs, genetic modification or diseases on the transcriptional machinery. The comparisons between GES profiles have been used to investigate the relationships between drugs, their targets and diseases with quite a few successful cases reported. Especially in the study of GES-guided drugs-disease associations, researchers believe that if a GES induced by a drug is opposite to a GES induced by a disease, the drug may have potential as a treatment of that disease. In this study, we data-mined the crowd extracted expression of differential signatures (CREEDS) database to evaluate the similarity between GES profiles from drugs and their indicated diseases. Our study aims to explore the application domains of GES-guided drug-disease associations through the analysis of the similarity of GES profiles on known pairs of drug-disease associations, thereby identifying subgroups of drugs/diseases that are suitable for GES-guided drug repositioning approaches. Our results supported our hypothesis that the GES-guided drug-disease association method is better suited for some subgroups or pathways such as drugs and diseases associated with the immune system, diseases of the nervous system, non-chemotherapy drugs or the mTOR signaling pathway.

Effects of Vitamin D Use on Outcomes of Psychotic Symptoms in Alzheimer Disease Patients.

OBJECTIVE: To identify medications that may prevent psychosis in patients with Alzheimer disease (AD). METHODS: The authors compared the frequency of medication usage among patients with AD with or without psychosis symptoms (AD + P versus AD - P). The authors also conducted survival analysis on time to psychosis for patients with AD to identify drugs with beneficial effects. The authors further explored the potential molecular mechanisms of identified drugs by gene-signature analysis. Specifically, the gene expression profiles induced by the identified drug(s) were collected to derive a list of most perturbed genes. These genes were further analyzed by the associations of their genetic variations with AD or psychosis-related phenotypes. RESULTS: Vitamin D was used more often in AD - P patients than in AD + P patients. Vitamin D was also significantly associated with delayed time to psychosis. AD and/or psychosis-related genes were enriched in the list of genes most perturbed by vitamin D, specifically genes involved in the regulation of calcium signaling downstream of the vitamin D receptor. CONCLUSION: Vitamin D was associated with delayed onset of psychotic symptoms in patients with AD. Its mechanisms of action provide a novel direction for development of drugs to prevent or treat psychosis in AD. In addition, genetic variations in vitamin D-regulated genes may provide a biomarker signature to identify a subpopulation of patients who can benefit from vitamin D treatment.

A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys.

BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state. METHODS: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-ᴅ-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components. RESULTS: Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components. LIMITATIONS: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex. CONCLUSION: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.

Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set.

INTRODUCTION: In 2015, the US Alzheimer's Disease Centers (ADC) implemented Version 3 of the Uniform Data Set (UDS). This paper describes the history of Version 3 development and the UDS data that are freely available to researchers. METHODS: UDS Version 3 was developed after years of coordination between the National Institute on Aging-appointed Clinical Task Force (CTF), clinicians from ∼30 ADCs, and the National Alzheimer's Coordinating Center (NACC). The CTF recognized the need for updates to align with the state of the science in dementia research, while being flexible to the diverse needs and diseases studied at the ADCs. Version 3 also developed a nonproprietary neuropsychological battery. RESULTS: This paper focuses on the substantial Version 3 changes to the UDS forms related to clinical diagnosis and characterization of clinical symptoms to match updated consensus-based diagnostic criteria. Between March 2015 and March 2018, 4820 participants were enrolled using UDS Version 3. Longitudinal data were available for 25,337 of the 37,568 total participants using all UDS versions. DISCUSSION: The results from utilization of the UDS highlight the possibility for numerous research institutions to successfully collaborate, produce, and use standardized data collection instruments for over a decade.

Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease.

It has been hypothesized that Alzheimer disease (AD) is primarily a disorder of the synapse. However, assessment of the synaptic proteome in AD subjects has been limited to a small number of proteins and often included subjects with end-stage pathology. Protein from prefrontal cortex gray matter of 59 AD subjects with mild to moderate dementia and 12 normal elderly subjects was assayed using targeted mass spectrometry to quantify 191 synaptically expressed proteins. The profile of synaptic protein expression clustered AD subjects into two groups. One of these was characterized by reduced expression of glutamate receptor proteins, significantly increased synaptic protein network coexpression, and associated withApolipoprotein E*4 (APOE*4) carrier status. The second group, by contrast, showed few differences from control subjects. A subset of AD subjects had altered prefrontal cortex synaptic proteostasis for glutamate receptors and their signaling partners. Efforts to therapeutically target glutamate receptors in AD may have outcomes dependent on APOE*4 genotype.

A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys.

BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state. METHODS: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-d-aspartate receptor channel blockers ketamine and MK-801 as well as the γ-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components. RESULTS: Ketamine, MK-801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components. LIMITATIONS: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex. CONCLUSION: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive.

FastGGM: An Efficient Algorithm for the Inference of Gaussian Graphical Model in Biological Networks.

Biological networks provide additional information for the analysis of human diseases, beyond the traditional analysis that focuses on single variables. Gaussian graphical model (GGM), a probability model that characterizes the conditional dependence structure of a set of random variables by a graph, has wide applications in the analysis of biological networks, such as inferring interaction or comparing differential networks. However, existing approaches are either not statistically rigorous or are inefficient for high-dimensional data that include tens of thousands of variables for making inference. In this study, we propose an efficient algorithm to implement the estimation of GGM and obtain p-value and confidence interval for each edge in the graph, based on a recent proposal by Ren et al., 2015. Through simulation studies, we demonstrate that the algorithm is faster by several orders of magnitude than the current implemented algorithm for Ren et al. without losing any accuracy. Then, we apply our algorithm to two real data sets: transcriptomic data from a study of childhood asthma and proteomic data from a study of Alzheimer's disease. We estimate the global gene or protein interaction networks for the disease and healthy samples. The resulting networks reveal interesting interactions and the differential networks between cases and controls show functional relevance to the diseases. In conclusion, we provide a computationally fast algorithm to implement a statistically sound procedure for constructing Gaussian graphical model and making inference with high-dimensional biological data. The algorithm has been implemented in an R package named "FastGGM".

GABA-Synthesizing Enzymes in Calbindin and Calretinin Neurons in Monkey Prefrontal Cortex.

Non-overlapping groups of cortical γ-aminobutyric acid-releasing (GABAergic) neurons are identifiable by the presence of calbindin (CB), calretinin (CR), or parvalbumin (PV). Boutons from PV neuron subtypes are also distinguishable by differences in protein levels of the GABA-synthesizing enzymes GAD65 and GAD67. Multilabel fluorescence microscopy was used to determine if this diversity extends to boutons of CB and CR neurons in monkey prefrontal cortex. CB and CR neurons gave rise to 3 subpopulations of GAD-containing boutons: GAD65+, GAD67+, and GAD65/GAD67+. Somatostatin and vasoactive intestinal peptide-expressing neurons, subtypes of CB and CR neurons, respectively, also gave rise to these distinct bouton subpopulations. At the transcript level, CB and CR neurons contained mRNA encoding GAD67-only or both GADs. Thus, the distinct subpopulations of CB/GAD+ and CR/GAD+ boutons arise from 2 unique subtypes of CB and CR neurons. The different CB and CR GAD-expressing neurons targeted the same projection neurons and neuronal structures immunoreactive for PV, CR, or CB. These findings suggest that GABA synthesis from CB/GAD67+ and CR/GAD67+ neurons would presumably be more vulnerable to disease-associated deficits in GAD67 expression, such as in schizophrenia, than neurons that also contain GAD65.

Developmental Trajectories of Auditory Cortex Synaptic Structures and Gap-Prepulse Inhibition of Acoustic Startle Between Early Adolescence and Young Adulthood in Mice.

Cortical excitatory and inhibitory synapses are disrupted in schizophrenia, the symptoms of which often emerge during adolescence, when cortical excitatory synapses undergo pruning. In auditory cortex, a brain region implicated in schizophrenia, little is known about the development of excitatory and inhibitory synapses between early adolescence and young adulthood, and how these changes impact auditory cortex function. We used immunohistochemistry and quantitative fluorescence microscopy to quantify dendritic spines and GAD65-expressing inhibitory boutons in auditory cortex of early adolescent, late adolescent, and young adult mice. Numbers of spines decreased between early adolescence and young adulthood, during which time responses increased in an auditory cortex-dependent sensory task, silent gap-prepulse inhibition of the acoustic startle reflex (gap-PPI). Within-bouton GAD65 protein and GAD65-expressing bouton numbers decreased between late adolescence and young adulthood, a delay in onset relative to spine and gap-PPI changes. In mice lacking the spine protein kalirin, there were no significant changes in spine number, within-bouton GAD65 protein, or gap-PPI between adolescence and young adulthood. These results illustrate developmental changes in auditory cortex spines, inhibitory boutons, and auditory cortex function between adolescence and young adulthood, and provide insights into how disrupted adolescent neurodevelopment could contribute to auditory cortex synapse pathology and auditory impairments.

Genetics of psychosis of Alzheimer disease.

Psychotic symptoms, comprised of delusions and hallucinations, occur in about half of individuals with Alzheimer disease (AD with psychosis, AD+P). These individuals have greater agitation, aggression, depression, functional impairment, and mortality than individuals without psychosis (AD-P). Although the exact etiopathogenesis of AD+P is unclear, the rapidly developing field of genomics continues to expand our understanding of this disease. Several independent studies have demonstrated familial aggregation and heritability of AD+P. Linkage studies have been suggestive of loci on several chromosomes associated with AD+P. Association studies examining apolipoprotein E gene, the best established genetic risk factor for late-onset AD, did not find any significant association of this gene with AD+P. Other candidate gene studies focusing on monoamine neurotransmitter systems have yielded equivocal results. A genome-wide association study and studies examining copy number variations recently have detected suggestive associations, but have been underpowered. Approaches to increase sizes of AD+P samples for genome wide association studies are discussed. © 2016 Wiley Periodicals, Inc.

Contextual processing in unpredictable auditory environments: the limited resource model of auditory refractoriness in the rhesus.

Auditory refractoriness refers to the finding of smaller electroencephalographic (EEG) responses to tones preceded by shorter periods of silence. To date, its physiological mechanisms remain unclear, limiting the insights gained from findings of abnormal refractoriness in individuals with schizophrenia. To resolve this roadblock, we studied auditory refractoriness in the rhesus, one of the most important animal models of auditory function, using grids of up to 32 chronically implanted cranial EEG electrodes. Four macaques passively listened to sounds whose identity and timing was random, thus preventing animals from forming valid predictions about upcoming sounds. Stimulus onset asynchrony ranged between 0.2 and 12.8 s, thus encompassing the clinically relevant timescale of refractoriness. Our results show refractoriness in all 8 previously identified middle- and long-latency components that peaked between 14 and 170 ms after tone onset. Refractoriness may reflect the formation and gradual decay of a basic sensory memory trace that may be mirrored by the expenditure and gradual recovery of a limited physiological resource that determines generator excitability. For all 8 components, results were consistent with the assumption that processing of each tone expends ∼65% of the available resource. Differences between components are caused by how quickly the resource recovers. Recovery time constants of different components ranged between 0.5 and 2 s. This work provides a solid conceptual, methodological, and computational foundation to dissect the physiological mechanisms of auditory refractoriness in the rhesus. Such knowledge may, in turn, help develop novel pharmacological, mechanism-targeted interventions.