This review implicates the left superior temporal gyrus and the left medial temporal lobe as key regions of structural difference in patients with schizophrenia, compared to healthy subjects. The diversity of regions reported in voxel-based morphometry studies is in part related to the choice of variables in the automated process, such as smoothing kernel size and linear versus affine transformation, as well as to differences in patient groups. Voxel-based morphometry can be used as an exploratory whole-brain approach to identify abnormal brain regions in schizophrenia, which should then be validated by using region-of-interest analyses.

Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.aggression ͉ antisocial ͉ functional MRI ͉ monoamine oxidase A ͉ serotonin

AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal graymatter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis. IntroductionDopaminergic abnormalities have long served as a major framework for understanding the pathophysiology as well as pharmacology of psychosis, such as schizophrenia, and also associated cognitive deficits, particularly those affecting executive function and working memory. Classically, D1 receptors, implicated in the maintenance of relevant information during the working memory delay period (1), couple through Gα s protein to stimulate the production of cAMP and the activity of PKA (2). Conversely, D2 receptors, which in neural models play critical roles marking salience, prediction errors, and updating and manipulating new information (3), couple through Gα i/o protein to reduce cAMP production and PKA activity (2). Downstream from PKA, dopamine-(DA-) and cAMPregulated phosphoprotein of molecular weight 32 (DARPP-32) is a key signaling integrator that regulates an array of subsequent neurophysiological processes (2). Genetic variation in DARPP-32 has recently been found to have an impact on normal human variation in frontostriatal cognitive performance, neostriatal volume and physiologic activation, and functional connectivity between striatum and prefrontal cortex; DARPP-32 has also been implicated in risk for schizophrenia (4). The cAMP/PKA/DARPP-32 pathway, however, is not the only molecular network that transduces DA signals in dopaminoceptive neurons (2).

BackgroundThere is increasing interest in the role of physical exercise as a therapeutic strategy for individuals with Alzheimer’s disease (AD). We assessed the effect of 26 weeks (6 months) of a supervised aerobic exercise program on memory, executive function, functional ability and depression in early AD.Methods and findingsThis study was a 26-week randomized controlled trial comparing the effects of 150 minutes per week of aerobic exercise vs. non-aerobic stretching and toning control intervention in individuals with early AD. A total of 76 well-characterized older adults with probable AD (mean age 72.9 [7.7]) were enrolled and 68 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. Neuropsychological tests and surveys were conducted at baseline,13, and 26 weeks to assess memory and executive function composite scores, functional ability (Disability Assessment for Dementia), and depressive symptoms (Cornell Scale for Depression in Dementia). Cardiorespiratory fitness testing and brain MRI was performed at baseline and 26 weeks. Aerobic exercise was associated with a modest gain in functional ability (Disability Assessment for Dementia) compared to individuals in the ST group (X2 = 8.2, p = 0.02). There was no clear effect of intervention on other primary outcome measures of Memory, Executive Function, or depressive symptoms. However, secondary analyses revealed that change in cardiorespiratory fitness was positively correlated with change in memory performance and bilateral hippocampal volume.ConclusionsAerobic exercise in early AD is associated with benefits in functional ability. Exercise-related gains in cardiorespiratory fitness were associated with improved memory performance and reduced hippocampal atrophy, suggesting cardiorespiratory fitness gains may be important in driving brain benefits.Trial registrationClinicalTrials.gov NCT01128361

Neuroimaging studies of apolipoprotein E (APOEε4) have implicated its association with brain atrophy in Alzheimer's disease. To date, few studies have used automated morphological analysis techniques to assess APOEε4-related brain structure change in both gray and white matter in nondemented older adults. Nondemented (CDR = 0, n = 53) subjects over 60 had MRI, diffusion tensor imaging, and neurocognitive assessments. We assessed differences in cognition and brain structure associated with APOEε4 genetic variation using voxel-based morphometry techniques, and tract-based spatial statistics of fractional anisotropy change. In nondemented older adults with the ε4 allele, cognitive performance was reduced, and atrophy was present in the hippocampus and amygdala compared to APOEε4 negative participants. We also report that ε4 carriers have decreased fractional anisotropy in the left parahippocampal gyrus white matter. In conclusion, the presence of an APOEε4 allele in nondemented older adults is associated with decreases in cognition and gray and white matter changes in the medial temporal cortex. Overall we provide further evidence of the effects of genetic variance related to imaging and cognitive measures of risk for Alzheimer's disease.

Exercise and cardiorespiratory (CR) fitness may moderate age-related regional brain changes in nondemented older adults (ND). The relationship of fitness to Alzheimer's disease (AD) related brain change is understudied, particularly in the hippocampus which is disproportionately affected in early AD. The role of apolipoprotein E4 (apoE4) genotype in modulating this relationship is also unknown. Nondemented (n=56) and early-stage AD subjects (n=61) over age 65 had MRI and CR fitness assessments. Voxel-based morphometry (VBM) techniques were utilized to identify AD-related atrophy. We analyzed the relationship of CR fitness with white and gray matter within groups, assessed fitness-related brain volume change in areas most affected by AD-related atrophy, and then analyzed differential fitness-brain relationships between apoE4 carriers. Atrophy was present in the medial temporal, temporal, and parietal cortices in subjects with mild AD. There was a significant positive correlation of CR fitness with parietal and medial temporal volume in AD subjects. ND subjects did not have a significant relationship between brain volume and CR fitness in the global or SVC analyses. There was not a significant interaction for fitness × apoE4 genotype in either group. In early-stage AD, cardiorespiratory fitness is associated with regional brain volumes in the medial temporal and parietal cortices suggesting that maintaining cardiorespiratory fitness may modify ADrelated brain atrophy.

Although Alzheimer’s Disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease –modifying therapies.

Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia.