Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia.

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters-glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids-and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate 'slow' (G-protein-coupled receptors) and 'fast' (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an 'associative' disorder-a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways-and may unify a number of currently competing hypotheses of SCZ pathophysiology.

Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci.

Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21,856) and multiple sclerosis (MS) (n=43,879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16,731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

Entorhinal Cortex: Antemortem Cortical Thickness and Postmortem Neurofibrillary Tangles and Amyloid Pathology.

BACKGROUND AND PURPOSE: The entorhinal cortex, a critical gateway between the neocortex and hippocampus, is one of the earliest regions affected by Alzheimer disease-associated neurofibrillary tangle pathology. Although our prior work has automatically delineated an MR imaging-based measure of the entorhinal cortex, whether antemortem entorhinal cortex thickness is associated with postmortem tangle burden within the entorhinal cortex is still unknown. Our objective was to evaluate the relationship between antemortem MRI measures of entorhinal cortex thickness and postmortem neuropathological measures. MATERIALS AND METHODS: We evaluated 50 participants from the Rush Memory and Aging Project with antemortem structural T1-weighted MR imaging and postmortem neuropathologic assessments. Here, we focused on thickness within the entorhinal cortex as anatomically defined by our previously developed MR imaging parcellation system (Desikan-Killiany Atlas in FreeSurfer). Using linear regression, we evaluated the association between entorhinal cortex thickness and tangles and amyloid-ß load within the entorhinal cortex and medial temporal and neocortical regions. RESULTS: We found a significant relationship between antemortem entorhinal cortex thickness and entorhinal cortex (P = .006) and medial temporal lobe tangles (P = .002); we found no relationship between entorhinal cortex thickness and entorhinal cortex (P = .09) and medial temporal lobe amyloid-ß (P = .09). We also found a significant association between entorhinal cortex thickness and cortical tangles (P = .003) and amyloid-ß (P = .01). We found no relationship between parahippocampal gyrus thickness and entorhinal cortex (P = .31) and medial temporal lobe tangles (P = .051). CONCLUSIONS: Our findings indicate that entorhinal cortex-associated in vivo cortical thinning may represent a marker of postmortem medial temporal and neocortical Alzheimer disease pathology.

In vivo prostate cancer detection and grading using restriction spectrum imaging-MRI.

BACKGROUND: Magnetic resonance imaging (MRI) is emerging as a robust, noninvasive method for detecting and characterizing prostate cancer (PCa), but limitations remain in its ability to distinguish cancerous from non-cancerous tissue. We evaluated the performance of a novel MRI technique, restriction spectrum imaging (RSI-MRI), to quantitatively detect and grade PCa compared with current standard-of-care MRI. METHODS: In a retrospective evaluation of 33 patients with biopsy-proven PCa who underwent RSI-MRI and standard MRI before radical prostatectomy, receiver-operating characteristic (ROC) curves were performed for RSI-MRI and each quantitative MRI term, with area under the ROC curve (AUC) used to compare each term's ability to differentiate between PCa and normal prostate. Spearman rank-order correlations were performed to assess each term's ability to predict PCa grade in the radical prostatectomy specimens. RESULTS: RSI-MRI demonstrated superior differentiation of PCa from normal tissue, with AUC of 0.94 and 0.85 for RSI-MRI and conventional diffusion MRI, respectively (P=0.04). RSI-MRI also demonstrated superior performance in predicting PCa aggressiveness, with Spearman rank-order correlation coefficients of 0.53 (P=0.002) and -0.42 (P=0.01) for RSI-MRI and conventional diffusion MRI, respectively, with tumor grade. CONCLUSIONS: RSI-MRI significantly improves upon current noninvasive PCa imaging and may potentially enhance its diagnosis and characterization.

Higher rates of decline for women and apolipoprotein E epsilon4 carriers.

BACKGROUND AND PURPOSE: Age and the apolipoprotein E ε4 allele are well-known risk factors for Alzheimer disease, but whether female sex is also a risk factor remains controversial. It is also unclear how these risk factors affect rates of structural brain and clinical decline across the spectrum of preclinical to clinical Alzheimer disease. Our objective is to estimate the effects of apolipoprotein E ε4 and sex on age-specific rates of morphometric and clinical decline in late-onset sporadic Alzheimer disease. MATERIALS AND METHODS: With the use of linear mixed-effects models, we examined the effect of age, apolipoprotein E ε4, and sex on longitudinal brain atrophy and clinical decline among cognitively normal older individuals and individuals with mild cognitive impairment and Alzheimer disease (total = 688). We also evaluated the relationship between these effects and CSF biomarkers of Alzheimer disease pathology. RESULTS: Apolipoprotein E ε4 significantly accelerated rates of decline, and women in all cohorts had higher rates of decline than men. The magnitude of the sex effect on rates of decline was as large as those of ε4, yet their relationship to measures of CSF biomarkers were weaker. CONCLUSIONS: These results indicate that in addition to apolipoprotein E ε4 status, diagnostic and therapeutic strategies should take into account the effect of female sex on the Alzheimer disease process.

An expanded role for neuroimaging in the evaluation of memory impairment.

SUMMARY: Alzheimer disease affects millions of people worldwide. The neuropathologic process underlying this disease begins years, if not decades, before the onset of memory decline. Recent advances in neuroimaging suggest that it is now possible to detect Alzheimer-associated neuropathologic changes well before dementia onset. Here, we evaluate the role of recently developed in vivo biomarkers in the clinical evaluation of Alzheimer disease. We discuss how assessment strategies might incorporate neuroimaging markers to better inform patients, families, and clinicians when memory impairment prompts a search for diagnosis and management options.

Apolipoprotein E epsilon4 does not modulate amyloid-ß-associated neurodegeneration in preclinical Alzheimer disease.

BACKGROUND AND PURPOSE: Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aß and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aß, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD. MATERIALS AND METHODS: We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aß(1-42), CSF p-τ and CSF Aß(1-42), and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aß(1-42) on the atrophy rate of other AD-vulnerable neuroanatomic regions. RESULTS: The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aß(1-42) on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aß(1-42). The APOE ε4 genotype was significantly and specifically associated with CSF Aß(1-42). However, the interaction between the APOE ε4 genotype and either CSF Aß(1-42) or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions. CONCLUSIONS: On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aß-related mechanisms, and in turn, Aß-associated neurodegeneration occurs only in the presence of p-τ.

Temporoparietal MR imaging measures of atrophy in subjects with mild cognitive impairment that predict subsequent diagnosis of Alzheimer disease.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) represents a transitional state between normal aging and Alzheimer disease (AD). Our goal was to determine if specific temporoparietal regions can predict the time to progress from MCI to AD. MATERIALS AND METHODS: MR images from 129 individuals with MCI were analyzed to identify the volume of 14 neocortical and 2 non-neocortical brain regions, comprising the temporal and parietal lobes. In addition, 3 neuropsychological test scores were included to determine whether they would provide independent information. After a mean follow-up time of 5 years, 44 of these individuals had progressed to a diagnosis of AD. RESULTS: Cox proportional hazards models demonstrated significant effects for 6 MR imaging regions with the greatest differences being the following: the entorhinal cortex (hazard ratio [HR] = 0.54, P < .001), inferior parietal lobule (hazard ratio [HR] = 0.64, P < .005), and middle temporal gyrus (HR = 0.64, P < .004), indicating decreased risk with larger volumes. A multivariable model showed that a combination of the entorhinal cortex (HR = 0.60, P < .001) and the inferior parietal lobule (HR = 0.62, P < .01) was the best predictor of time to progress to AD. A multivariable model reiterated the importance of including both MR imaging and neuropsychological variables in the final model. CONCLUSIONS: These findings reaffirm the importance of the entorhinal cortex and present evidence for the importance of the inferior parietal lobule as a predictor of time to progress from MCI to AD. The inclusion of neuropsychological performance in the final model continues to highlight the importance of using these measures in a complementary fashion.

MRI measures of temporoparietal regions show differential rates of atrophy during prodromal AD.

BACKGROUND: MRI studies have demonstrated differential rates of atrophy in the entorhinal cortex and hippocampus during the prodromal phase of Alzheimer disease (AD). The current study was designed to determine whether a broader set of temporoparietal regions show differential rates of atrophy during the evolution of AD. METHODS: Sixteen regions of interest (ROIs) were analyzed on MRI scans obtained at baseline and follow-up in 66 subjects comprising three groups: controls = individuals who were cognitively normal at both baseline and follow-up; nonconverters = subjects with mild cognitive impairment (MCI) at both baseline and follow-up; converters had MCI at baseline but had progressed to AD at follow-up. RESULTS: Annualized percent change was analyzed with multivariate analysis of variance (MANOVA), covaried for age. The MANOVA demonstrated an effect of group (p = 0.004). Post hoc comparisons demonstrated greater rates of atrophy for converters vs nonconverters for six ROIs: hippocampus, entorhinal cortex, temporal pole, middle temporal gyrus, fusiform gyrus, and inferior temporal gyrus. Converters showed differentially greater rates of atrophy than controls in five of the same ROIs (and inferior parietal lobule). Rates of change in clinical status were correlated with the atrophy rates in these regions. Comparisons between controls and nonconverters demonstrated no differences. CONCLUSION: These results demonstrate that temporoparietal regions show differential rates of atrophy on MRI during prodromal Alzheimer disease (AD). MRI data correlate with measures of clinical severity and cognitive decline, suggesting the potential of these regions of interest as antemortem markers of prodromal AD.