Neurodevelopment & risk factors in schizophrenia

Schizophrenia is a complex psychiatric disorder with positive, negative, and cognitive symptoms. The causes are not yet fully understood, but it is believed that together with a strong genetic foundation, a ‘second environmental hit’ may be responsible to triggering a psychotic episode. Early-onset schizophrenia (EOS) a rare and more severe form of the disorder compared to its adult-onset counterpart and it is regarded to be more genetically loaded. This being as children and adolescents are less likely to have accumulated environmental triggers that are often considered risks to develop schizophrenia. Neurotic personality and anxiety symptoms are considered candidate schizophrenia risk factors. Working memory (WM) performance, the ability to hold information “online” in the matter of a few seconds, as well as its neural correlates are severely impaired in EOS, and such impairment is considered endophenotypic to the disorder. In addition, the expression of neurophysiological indices of cognition such as the mismatch negativity (MMN) and P300 event-related potentials (ERPs) are consistently demonstrated to be reliable biomarkers for the disorder, as shown by electroencephalography. This thesis on one hand, explores the influence of neuroticism and anxiety levels in healthy participants in ERPs during the auditory roving oddball and the hollow mask illusion experiments that are continually shown to be affected in schizophrenia literature. On the other hand, it explores meta-analytically convergent structural and functional brain abnormalities in EOS literature and follows a longitudinal fMRI cohort of EOS and healthy adolescents who were scanned twice in a 4-year span, while they performed the n-back task (WM task). These experiments are aimed to reveal brain areas that may qualify as endophenotypic markers of impaired WM neurodevelopment in schizophrenia. Our results showed that anxiety and neuroticism do not fully explain their status as schizophrenia risk factors by their relationship with the schizophrenia biomarker ERPs (P50 sensory gating, MMN, P300 and P600). The meta- analysis strongly indicates that a dysfunction in the functional network that underlies salience and other executive functions related to incentive and goal-oriented processes may be central across cognitive paradigms in EOS. Longitudinally, functional connectivity and maturation impairments are prevalent in the WM functional substrate of adolescents with EOS as they undergo neurodevelopmental processes by transitioning into early adulthood

A Splicing Mutation in the Novel Mitochondrial Protein DNAJC11 Causes Motor Neuron Pathology Associated with Cristae Disorganization, and Lymphoid Abnormalities in Mice

Mitochondrial structure and function is emerging as a major contributor to neuromuscular disease, highlighting the need for the complete elucidation of the underlying molecular and pathophysiological mechanisms. Following a forward genetics approach with N-ethyl-N-nitrosourea (ENU)-mediated random mutagenesis, we identified a novel mouse model of autosomal recessive neuromuscular disease caused by a splice-site hypomorphic mutation in a novel gene of unknown function, DnaJC11. Recent findings have demonstrated that DNAJC11 protein co-immunoprecipitates with proteins of the mitochondrial contact site (MICOS) complex involved in the formation of mitochondrial cristae and cristae junctions. Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. The causal role of the identified mutation in DnaJC11 was verified in rescue experiments by overexpressing the human ortholog. The full length 63 kDa isoform of human DNAJC11 was shown to localize in the periphery of the mitochondrial outer membrane whereas putative additional isoforms displayed differential submitochondrial localization. Moreover, we showed that DNAJC11 is assembled in a high molecular weight complex, similarly to mitofilin and that downregulation of mitofilin or SAM50 affected the levels of DNAJC11 in HeLa cells. Our findings provide the first mouse mutant for a putative MICOS protein and establish a link between DNAJC11 and neuromuscular diseases

A Meta-analysis of Structural and Functional Brain Abnormalities in Early-Onset Schizophrenia

Early-onset schizophrenia (EOS) patients demonstrate brain changes that are similar to severe cases of adult-onset schizophrenia. Neuroimaging research in EOS is limited due to the rarity of the disorder. The present meta-analysis aims to consolidate MRI and functional MRI findings in EOS. Seven voxel-based morphometry (VBM) and 8 functional MRI studies met the inclusion criteria, reporting whole-brain analyses of EOS vs healthy controls. Activation likelihood estimation (ALE) was conducted to identify aberrant anatomical or functional clusters across the included studies. Separate ALE analyses were performed, first for all task-dependent studies (Cognition ALE) and then only for working memory ones (WM ALE). The VBM ALE revealed no significant clusters for gray matter volume reductions in EOS. Significant hypoactivations peaking in the right anterior cingulate cortex (rACC) and the right temporoparietal junction (rTPJ) were detected in the Cognition ALE. In the WM ALE, consistent hypoactivations were found in the left precuneus (lPreC), the right inferior parietal lobule (rIPL) and the rTPJ. These hypoactivated areas show strong associations with language, memory, attention, spatial, and social cognition. The functional co-activated networks of each suprathreshold ALE cluster, identified using the BrainMap database, revealed a core co-activation network with similar topography to the salience network. Our results add support to posterior parietal, ACC and rTPJ dysfunction in EOS, areas implicated in the cognitive impairments characterizing EOS. The salience network lies at the core of these cognitive processes, co-activating with the hypoactivating regions, and thus highlighting the importance of salience dysfunction in EOS

Functional neurodevelopment of working memory in early-onset schizophrenia: A longitudinal FMRI study

Schizophrenia, a debilitating disorder with typical manifestation of clinical symptoms in early adulthood, is characterized by cognitive impairments in executive processes such as in working memory (WM). However, there is a rare case of individuals with early-onset schizophrenia (EOS) starting before their 18th birthday, while WM and its neural substrates are still undergoing maturation. Using the WM n-back task with functional magnetic resonance imaging, we assessed the functional neurodevelopment of WM in adolescents with EOS and age- and gender-matched typically developing controls. Participants underwent neuroimaging in the same scanner twice, once at age 17 and at 21 (mean interscan interval = 4.3 years). General linear model analysis was performed to explore WM neurodevelopmental changes within and between groups. Psychopathological scores were entered in multiple regressions to detect brain regions whose longitudinal functional change was predicted by baseline symptoms in EOS. WM neurodevelopment was characterized by widespread functional reductions in frontotemporal and cingulate brain areas in patients and controls. No between-group differences were found in the trajectory of WM change. Baseline symptom scores predicted functional neurodevelopmental changes in frontal, cingulate, parietal, occipital, and cerebellar areas. The adolescent brain undergoes developmental processes such as synaptic pruning, which may underlie the refinement WM of network. Prefrontal and parietooccipital activity reduction is affected by clinical presentation of symptoms. Using longitudinal neuroimaging methods in a rare diagnostic sample of patients with EOS may help the advancement of neurodevelopmental biomarkers intended as pharmacological targets to tackle WM impairment

Trait and State Anxiety Effects on Mismatch Negativity and Sensory Gating Event-Related Potentials

We used the auditory roving oddball to investigate whether individual differences in self-reported anxiety influence event-related potential (ERP) activity related to sensory gating and mismatch negativity (MMN). The state-trait anxiety inventory (STAI) was used to assess the effects of anxiety on the ERPs for auditory change detection and information filtering in a sample of thirty-six healthy participants. The roving oddball paradigm involves presentation of stimulus trains of auditory tones with certain frequencies followed by trains of tones with different frequencies. Enhanced negative mid-latency response (130–230 ms post-stimulus) was marked at the deviant (first tone) and the standard (six or more repetitions) tone at Fz, indicating successful mismatch negativity (MMN). In turn, the first and second tone in a stimulus train were subject to sensory gating at the Cz electrode site as a response to the second stimulus was suppressed at an earlier latency (40–80 ms). We used partial correlations and analyses of covariance to investigate the influence of state and trait anxiety on these two processes. Higher trait anxiety exhibited enhanced MMN amplitude (more negative) (F(1,33) = 14.259, p = 6.323 × 10−6, ηp2 = 0.302), whereas state anxiety reduced sensory gating (F(1,30) = 13.117, p = 0.001, ηp2 = 0.304). Our findings suggest that high trait-anxious participants demonstrate hypervigilant change detection to deviant tones that appear more salient, whereas increased state anxiety associates with failure to filter out irrelevant stimuli

State anxiety influences P300 and P600 event-related potentials over parietal regions in the hollow-mask illusion experiment

The hollow-mask illusion is an optical illusion where a concave face is perceived as convex. It has been demonstrated that individuals with schizophrenia and anxiety are less susceptible to the illusion than controls. Previous research has shown that the P300 and P600 event-related potentials (ERPs) are affected in individuals with schizophrenia. Here, we examined whether individual differences in neuroticism and anxiety scores, traits that have been suggested to be risk factors for schizophrenia and anxiety disorders, affect ERPs of healthy participants while they view concave faces. Our results confirm that the participants were susceptible to the illusion, misperceiving concave faces as convex. We additionally demonstrate significant interactions of the concave condition with state anxiety in central and parietal electrodes for P300 and parietal areas for P600, but not with neuroticism and trait anxiety. The state anxiety interactions were driven by low-state anxiety participants showing lower amplitudes for concave faces compared to convex. The P300 and P600 amplitudes were smaller when a concave face activated a convex face memory representation, since the stimulus did not match the active representation. The opposite pattern was evident in high-state anxiety participants in regard to state anxiety interaction and the hollow-mask illusion, demonstrating larger P300 and P600 amplitudes to concave faces suggesting impaired late information processing in this group. This could be explained by impaired allocation of attentional resources in high-state anxiety leading to hyperarousal to concave faces that are unexpected mismatches to standard memory representations, as opposed to expected convex faces

Acute effect of coffee on aortic stiffness and wave reflections in healthy individuals: differential effect according to habitual consumption

The acute effect of coffee on arterial stiffness and its dependence on habitual consumption was studied in 24 volunteers on four separate occasions during which subjects received: (a) coffee espresso, (b) decaffeinated coffee espresso, (c) caffeine alone and (d) placebo (hot water). The increase in carotid femoral pulse wave velocity (PWV), augmentation index (AIx) and augmented pressure (AP) of the aortic pressure waveform after coffee consumption was more pronounced in non-habitual (n = 13) compared to habitual drinkers (n = 11), (differences of maximal changes between groups in PWV, AIx, AP responses by 0.39 m/s, 4.5% and 1.9 mmHg, respectively, for coffee; and by 0.34 m/s, 5.3% and 2.1 mmHg, respectively, for decaffeinated coffee; all p <.05). Caffeine increased PWV, as well as AIx and AP but differences in responses between the two groups were not significant. Both caffeinated and decaffeinated coffee consumption is associated with a more potent effect on arterial stiffness in non-habitual than habitual coffee consumers, whereas caffeine induces comparable changes in both groups. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group

Statin Therapy and Risk of Diabetes Mellitus in Aging Patients With Heterozygous Familial Hypercholesterolemia or Familial Combined Hyperlipidemia: A 10-Year Follow-Up

We assessed the incidence of diabetes mellitus (DM) in patients with heterozygous familial hypercholesterolemia (HeFH) and familial combined hyperlipidemia (FCH) treated with statins. Participants (n = 280) of mean age 59 ± 5 years were included (90 patients with HeFH, 112 patients with FCH, and 78 aged-matched participants). The median statin intensity treatment product (statin intensity in arbitrary equivalence units × duration of statin therapy in months) was 119 and 85 for patients with HeFH and FCH, respectively, at 10-year follow-up. The incidence of DM was significantly lower in patients with HeFH compared to the patients with FCH (2% vs 20%) and the reference group (2% vs 17%) during the 10-year follow-up period (all Ps <.001). Impaired fasting blood glucose at entry (P <.001) and central obesity (P =.02) were the only independent predictors of DM. The incidence of DM was significantly lower in older patients with HeFH compared to either aged-matched patients with FCH or individuals not receiving statins. Statins did not increase risk of DM in aging patients with FCH. These findings have implications, given the importance of high-intensity statin therapy for prevention of cardiovascular events, especially in patients with HeFH, a population with high cardiovascular risk. © 2017, © The Author(s) 2017

Prediction of Cardiovascular Events and All-Cause Mortality With Erectile Dysfunction A Systematic Review and Meta-Analysis of Cohort Studies

Background-Erectile dysfunction (ED) carries an independent risk for cardiovascular (CV) events. We conducted a meta-analysis of all longitudinal studies for determining the ability of ED to predict risk of clinical events and to dissect factors influencing this ability. Methods and Results-We conducted a comprehensive search of electronic databases through July 2012. Longitudinal studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) were included. Of the 14 studies included (92 757 participants; mean follow-up, 6.1 years; 16 articles), 13 (14 articles) reported results on total CV events (91 831 individuals), 4 on CV mortality (34 761 individuals), 4 on myocardial infarction (35 523 individuals), 6 on cerebrovascular events (27 689 individuals), and 5 on all-cause mortality (17 869 individuals). The pooled RRs for the above-mentioned end points were 1.44 (95% CI, 1.27-1.63), 1.19 (95% CI, 0.97-1.46), 1.62 (95% CI, 1.34-1.96), 1.39 (95% CI, 1.23-1.57), and 1.25 (95% CI, 1.12-1.39), respectively, for men with versus without ED. The RR was higher in intermediate-compared with high-or low-CV-risk populations and with younger age. The RR for studies that diagnosed ED with the use of a questionnaire compared with a single question was higher (RR, 1.61; 95% CI, 1.38-1.86 versus RR, 1.27; 95% CI, 1.18-1.37, respectively; P=0.006). Conclusions-ED is associated with increased risk of CV events and all-cause mortality. RR is higher at younger ages, in intermediate-risk groups, and when a questionnaire is used instead of a single question. (Circ Cardiovasc Qual Outcomes. 2013; 6: 99-109.