The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Genetics of environmental sensitivity to psychiatric and neurodevelopmental phenotypes: evidence from GWAS of monozygotic twins.

Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes. However, environmental sensitivity genetic variants have proven challenging to detect. GWAS of monozygotic twin differences is a family-based variance analysis method, which is more robust to systemic biases that impact population-based methods. We combined data from up to 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct the largest GWAS meta-analysis of monozygotic phenotypic differences in children and adolescents/adults for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder (ADHD) symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism, and wellbeing. The SNP-heritability of variance in these phenotypes were estimated (h2: 0% to 18%), but were imprecise. We identified a total of 13 genome-wide significant associations (SNP, gene, and gene-set), including genes related to stress-reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. Monozygotic twins are an important new source of evidence about the genetics of environmental sensitivity.

Heritability of Gene Expression Measured from Peripheral Blood in Older Adults.

The contributions of genetic variation and the environment to gene expression may change across the lifespan. However, few studies have investigated the heritability of blood gene expression in older adults. The current study therefore aimed to investigate this question in a community sample of older adults. A total of 246 adults (71 MZ and 52 DZ twins, 69.91% females; mean age-75.79 ± 5.44) were studied. Peripheral blood gene expression was assessed using Illumina microarrays. A heritability analysis was performed using structural equation modelling. There were 5269 probes (19.9%) from 4603 unique genes (23.9%) (total 26,537 probes from 19,256 genes) that were significantly heritable (mean h2 = 0.40). A pathway analysis of the top 10% of significant genes showed enrichment for the immune response and ageing-associated genes. In a comparison with two other gene expression twin heritability studies using adults from across the lifespan, there were 38 out of 9479 overlapping genes that were significantly heritable. In conclusion, our study found ~24% of the available genes for analysis were heritable in older adults, with only a small number common across studies that used samples from across adulthood, indicating the importance of examining gene expression in older age groups.

Age and Sex Differences in the Genetic Architecture of Measures of Subjective Health: Relationships With Physical Health, Depressive Symptoms, and Episodic Memory.

OBJECTIVES: Subjective health (SH) is not just an indicator of physical health, but also reflects active cognitive processing of information about one's own health and has been associated with emotional health measures, such as neuroticism and depression. Behavior genetic approaches investigate the genetic architecture of SH, that is, genetic and environmental influences on individual differences in SH and associations with potential components such as physical, cognitive, and emotional health. Previous twin analyses have been limited by sex, sample size, age range, and focus on single covariates. METHODS: The current analysis used data from 24,173 adults ranging in age from 40 to 90 years from the international Interplay of Genes and Environment across Multiple Studies consortium to investigate the genetic architecture of 3 measures of SH: self-rated health, health compared to others, and impact of health on activities. Independent pathways model of SH included physical health, depressive symptoms, and episodic memory, with age, sex, and country included as covariates. RESULTS: Most or all of the genetic variance for SH measures were shared with physical health, depressive symptoms, and episodic memory. Genetic architecture of SH differed across measures, age groups (40-65, 66-90), and sexes. Age comparisons indicated stronger correlations with all 3 covariates in older adults, often resulting from greater shared genetic variance. DISCUSSION: The predictive value of SH has been amply demonstrated. The higher genetic contributions to associations between SH and its components in older adults support the increasing conceptualization with age of SH as an intuitive summation of one's vital reserve.

Molecular biomarkers for vascular cognitive impairment and dementia.

As disease-specific interventions for dementia are being developed, the ability to identify the underlying pathology and dementia subtypes is increasingly important. Vascular cognitive impairment and dementia (VCID) is the second most common cause of dementia after Alzheimer disease, but progress in identifying molecular biomarkers for accurate diagnosis of VCID has been relatively limited. In this Review, we examine the roles of large and small vessel disease in VCID, considering the underlying pathophysiological processes that lead to vascular brain injury, including atherosclerosis, arteriolosclerosis, ischaemic injury, haemorrhage, hypoperfusion, endothelial dysfunction, blood-brain barrier breakdown, inflammation, oxidative stress, hypoxia, and neuronal and glial degeneration. We consider the key molecules in these processes, including proteins and peptides, metabolites, lipids and circulating RNA, and consider their potential as molecular biomarkers alone and in combination. We also discuss the challenges in translating the promise of these biomarkers into clinical application.

Remember This: Age Moderation of Genetic and Environmental Contributions to Verbal Episodic Memory from Midlife through Late Adulthood.

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall (N = 35,204 individuals; 21,792 twin pairs) and prose recall (N = 3,805 individuals; 2,028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning.

Genetic and environmental influences on fruit and vegetable consumption and depression in older adults.

BACKGROUND: Prior work suggests that higher fruit and vegetable consumption may protect against depression in older adults. Better understanding of the influence of genetic and environmental factors on fruit and vegetable intakes may lead to the design of more effective dietary strategies to increase intakes. In turn this may reduce the occurrence of depression in older adults. OBJECTIVES: The primary aim of this study is to estimate the genetic and environmental influences on the consumption of fruit and vegetables in older adults. The secondary aim is an exploratory analysis into possible shared genetic influences on fruit and vegetable intakes and depression. METHODS: Analysis of observational data from 374 twins (67.1% female; 208 monozygotic (MZ); 166 dizygotic (DZ)) aged ≥ 65 years drawn from the Older Australian Twins Study. Dietary data were obtained using a validated food frequency questionnaire and depressive symptoms were measured using the 15-item short form Geriatric Depression Scale. The contribution of genetic and environmental influences on fruit and vegetable intake were estimated by comparing MZ and DZ twin intakes using structural equation modelling. A tri-variate twin model was used to estimate the genetic and environmental correlation between total fruit and vegetable intakes and depression. RESULTS: In this study, vegetable intake was moderately influenced by genetics (0.39 95%CI 0.22, 0.54). Heritability was highest for brassica vegetables (0.40 95%CI 0.24, 0.54). Overall fruit intake was not significantly heritable. No significant genetic correlations were detected between fruit and vegetable intake and depressive symptoms. CONCLUSIONS: Vegetable consumption, particularly bitter tasting brassica vegetables, was significantly influenced by genetics, although environmental influences were also apparent. Consumption of fruit was only influenced by the environment, with no genetic influence detected, suggesting strategies targeting the food environment may be particularly effective for encouraging fruit consumption.

Establishing conversion of the 16-item Informant Questionnaire on Cognitive Decline in the Elderly scores into interval-level data across multiple samples using Rasch methodology.

BACKGROUND: The 16-item Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE-16) is a well-validated and widely-used measure of cognitive changes (CCs) among older adults. This study aimed to use Rasch methodology to establish psychometric properties of the IQCODE-16 and validate the existing ordinal-to-interval transformation algorithms across multiple large samples. METHODS: A Partial Credit Rasch model was employed to examine psychometric properties of the IQCODE-16 using data (n = 918) from two longitudinal studies of participants aged 57-99 years: the Older Australian Twins Study (n = 450) and the Canberra Longitudinal Study (n = 468), and reusing the Sydney Memory and Ageing Study (MAS) sample (n = 400). RESULTS: Initial analyses indicated good reliability for the IQCODE-16 (Person Separation Index range: 0.82-0.90). However, local dependency was identified between items, with several items showing misfit to the model. Replicating the existing Rasch solution could not reproduce the best Rasch model fit for all samples. Combining locally dependent items into three testlets resolved all misfit and local dependency issues and resulted in the best Rasch model fit for all samples with evidence of unidimensionality, strong reliability, and invariance across person factors. Accordingly, new ordinal-to-interval transformation algorithms were produced to convert the IQCODE-16 ordinal scores into interval data to improve the accuracy of its scores. CONCLUSIONS: The findings of this study support the reliability and validity of the IQCODE-16 in measuring CCs among older adults. New ordinal-to-interval conversion tables generated using samples from multiple independent datasets are more generalizable and can be used to enhance the precision of the IQCODE-16 without changing its original format. An easy-to-use converter has been made available for clinical and research use.

The Heritability of Subjective Cognitive Complaints in Older Australian Twins.

BACKGROUND: Subjective cognitive complaints (SCCs) may be a precursor to mild cognitive impairment (MCI) and dementia. OBJECTIVE: This study aimed to examine the heritability of SCCs, correlations between SCCs and memory ability, and the influence of personality and mood on these relationships. METHODS: Participants were 306 twin pairs. The heritability of SCCs and the genetic correlations between SCCs and memory performance, personality, and mood scores were determined using structural equation modelling. RESULTS: SCCs were low to moderately heritable. Memory performance, personality and mood were genetically, environmentally, and phenotypically correlated with SCCs in bivariate analysis. However, in multivariate analysis, only mood and memory performance had significant correlations with SCCs. Mood appeared to be related to SCCs by an environmental correlation, whereas memory performance was related to SCCs by a genetic correlation. The link between personality and SCCs was mediated by mood. SCCs had a significant amount of both genetic and environmental variances not explained by memory performance, personality, or mood. CONCLUSION: Our results suggest that SCCs are influenced both by a person's mood and their memory performance, and that these determinants are not mutually exclusive. While SCCs had genetic overlap with memory performance and environmental association with mood, much of the genetic and environmental components that comprised SCCs were specific to SCCs, though these specific factors are yet to be determined.

The Heritability of Kidney Function Using an Older Australian Twin Population.

Introduction: Twin studies are unique population models which estimate observed rather than inferred genetic components of complex traits. Nonmonogenic chronic kidney disease (CKD) is a complex disease process with strong genetic and environmental influences, amenable to twin studies. We aimed to assess the heritability of CKD using twin analysis and modeling within Older Australian Twin Study (OATS) data. Methods: OATS had 109 dizygotic (DZ) and 126 monozygotic (MZ) twin pairs with paired serum creatinine levels. Heritability of kidney function as estimated glomerular filtration rate (eGFR CKD Epidemiology Collaboration [CKD-EPI]) was modeled using the ACE model to estimate additive heritability (A), common (C), and unique (E) environmental factors. Intratwin pair analysis using mixed effects logistic regression allowed analysis of variation in eGFR from established CKD risk factors. Results: The median age was 69.71 (interquartile range 78.4-83.0) years, with 65% female, and a mean CKD-EPI of 82.8 ml/min (SD 6.7). The unadjusted ACE model determined kidney function to be 33% genetically determined (A), 18% shared genetic-environmental (C), and 49% because of unique environment (E). This remained unchanged when adjusted for age, hypertension, and sex. Hypertension was associated with eGFR; however, intertwin variance in hypertension did not explain variance in eGFR. Two or more hypertension medications were associated with decreased eGFR (P = 0.009). Conclusion: This study estimates observed heritability at 33%, notably higher than inferred heritability in genome-wide association study (GWAS) (7.1%-18%). Epigenetics and other genomic phenomena may explain this heritability gap. Difference in antihypertension medications explains part of unique environmental exposures, though discordance in hypertension and diabetes does not.

Financial strain moderates genetic influences on self-rated health: support for diathesis-stress model of gene-environment interplay.

Data from the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium were used to examine predictions of different models of gene-by-environment interaction to understand how genetic variance in self-rated health (SRH) varies at different levels of financial strain. A total of 11,359 individuals from 10 twin studies in Australia, Sweden, and the United States contributed relevant data, including 2,074 monozygotic and 2,623 dizygotic twin pairs. Age ranged from 22 to 98 years, with a mean age of 61.05 (SD = 13.24). A factor model was used to create a harmonized measure of financial strain across studies and items. Twin analyses of genetic and environmental variance for SRH incorporating age, age2, sex, and financial strain moderators indicated significant financial strain moderation of genetic influences on self-rated health. Moderation results did not differ across sex or country. Genetic variance for SRH increased as financial strain increased, matching the predictions of the diathesis-stress and social comparison models for components of variance. Under these models, environmental improvements would be expected to reduce genetically based health disparities.

The heritability of amyloid burden in older adults: the Older Australian Twins Study.

OBJECTIVE: To determine the proportional genetic contribution to the variability of cerebral ß-amyloid load in older adults using the classic twin design. METHODS: Participants (n=206) comprising 61 monozygotic (MZ) twin pairs (68 (55.74%) females; mean age (SD): 71.98 (6.43) years), and 42 dizygotic (DZ) twin pairs (56 (66.67%) females; mean age: 71.14 (5.15) years) were drawn from the Older Australian Twins Study. Participants underwent detailed clinical and neuropsychological evaluations, as well as MRI, diffusion tensor imaging (DTI) and amyloid PET scans. Fifty-eight participants (17 MZ pairs, 12 DZ pairs) had PET scans with 11Carbon-Pittsburgh Compound B, and 148 participants (44 MZ pairs, 30 DZ pairs) with 18Fluorine-NAV4694. Cortical amyloid burden was quantified using the centiloid scale globally, as well as the standardised uptake value ratio (SUVR) globally and in specific brain regions. Small vessel disease (SVD) was quantified using total white matter hyperintensity volume on MRI, and peak width of skeletonised mean diffusivity on DTI. Heritability (h2) and genetic correlations were measured with structural equation modelling under the best fit model, controlling for age, sex, tracer and scanner. RESULTS: The heritability of global amyloid burden was moderate (0.41 using SUVR; 0.52 using the centiloid scale) and ranged from 0.20 to 0.54 across different brain regions. There were no significant genetic or environmental correlations between global amyloid burden and markers of SVD. CONCLUSION: Amyloid deposition, the hallmark early feature of Alzheimer's disease, is under moderate genetic influence, suggesting a major environmental contribution that may be amenable to intervention.

Genetic and Environmental Influences on Semantic Verbal Fluency Across Midlife and Later Life.

Despite the relevance of semantic fluency measures to risk for dementia and psychiatric disorders, little is known about their genetic and environmental architecture in mid-to-late life. Participants represent 21,684 middle-aged and older adult twins (M = 60.84 years, SD = 11.21; Range 40-89) from six studies from three countries participating in the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium. All completed the same measure of semantic fluency (naming animals in 60 seconds). Results revealed small-to-moderate phenotypic associations with age and education, with education more strongly and positively associated with fluency performance in females than males. Heritability and environmental influences did not vary by age. Environmental variance was smaller with higher levels of education, but this effect was observed only in males. This is the largest study to examine the genetic and environmental architecture of semantic fluency, and the first to demonstrate that environmental influences vary based on levels of education.

Altered levels of immune cell adhesion molecules are associated with memory impairment in schizophrenia and healthy controls.

Increased cytokines and increased intercellular adhesion molecule-1 (ICAM1) found in the schizophrenia prefrontal cortex and in the blood may relate to cognitive deficits. Endothelial ICAM1 regulates immune cell trafficking into the brain by binding to integrins located on the surface of leukocytes. Whether the circulating levels of the main ICAM1 adhesion partners, lymphocyte-function associated antigen-1 (LFA1) and complement receptor 3 (CR3), both integrins, are altered in schizophrenia is unknown. Gene expressions of ICAM1, LFA1 and CR3 were measured in leukocytes from 86 schizophrenia patients and 77 controls. Participants were also administered cognitive testing to determine the extent to which cognitive ability was related to molecular measures of leukocyte adhesion. This cohort was previously stratified into inflammatory subgroups based on circulating cytokine mRNAs; thus, gene expressions were analysed by diagnosis and by inflammatory subgroups. Previously measured plasma ICAM1 protein was elevated in "high inflammation" schizophrenia compared to both "high" and "low inflammation" controls while ICAM1 mRNA was unchanged in leukocytes. LFA1 mRNA was decreased and CR3 mRNA was increased in leukocytes from people with schizophrenia compared to controls. LFA1 mRNA levels were positively correlated with working memory and elevated soluble ICAM1 was negatively correlated with verbal memory in schizophrenia. Altogether, some of the cognitive deficits in schizophrenia may be associated with altered expression of molecules that regulate immune cell trafficking.

Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation.

Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood-brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into "high inflammation" and "low inflammation" subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The "high inflammation" schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both "low inflammation" schizophrenia and "low inflammation" control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in "high inflammation" schizophrenia compared to both "low inflammation" schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of "high inflammation" schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.

Cerebral Blood Flow in Community-Based Older Twins Is Moderately Heritable: An Arterial Spin Labeling Perfusion Imaging Study.

Adequate cerebral blood flow (CBF) is necessary to maintain brain metabolism and function. Arterial spin labeling (ASL) is an emerging MRI technique offering a non-invasive and reliable quantification of CBF. The genetic basis of CBF has not been well documented, and one approach to investigate this is to examine its heritability. The current study aimed to examine the heritability of CBF using ASL data from a cohort of community-dwelling older twins (41 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs; age range, 65-93 years; 56.4% female). The results showed that the cortex had higher CBF than subcortical gray matter (GM) regions, and CBF in the GM regions of the anterior cerebral artery (ACA) territory was lower than that of the middle (MCA) and posterior (PCA) cerebral arteries. After accounting for the effects of age, sex and scanner, moderate heritability was identified for global CBF (h 2 = 0.611; 95% CI = 0.380-0.761), as well as for cortical and subcortical GM and the GM in the major arterial territories (h 2 = 0.500-0.612). Strong genetic correlations (GCs) were found between CBF in subcortical and cortical GM regions, as well as among the three arterial territories (ACA, MCA, PCA), suggesting a largely convergent genetic control for the CBF in brain GM. The moderate heritability of CBF warrants future investigations to uncover the genetic variants and genes that regulate CBF.

Differential expression of synaptic and interneuron genes in the aging human prefrontal cortex.

Altered inhibition-excitation balance is implicated in brain aging. We hypothesized that expression of 14 genes encoding proteins localized to synapses or interneurons would show age-related changes relative to 1 another in postmortem tissue from the prefrontal cortex of 37 individuals (18-78 years) and that synaptic or interneuron markers would be differentially correlated with human brain volumes across aging. The majority of genes examined were differentially expressed with age, most being downregulated. Expression of 3 interneuron-related genes was significantly negatively associated with age (calbindin, somatostatin, cholecystokinin), whereas 3 synapse-related genes showed significant age-related expression change (PSD95, GAP43, VGLUT1). On covarying for 2 glial markers (GFAP, IBA1), all 3 interneuron genes and 1 synaptic gene (Growth-associated protein 43) remained significant. Two genes were significantly associated with total brain volume (calbindin, complexin 2) and a marker of synaptic density (synaptophysin) was significantly associated with cortical gray matter volume. Age-related change in expression of genes involved in maintenance of inhibition-excitation balance and regulation of prefrontocortical network dynamics suggests these pathways may contribute to brain aging.

Nuclear Receptors and Neuroinflammation in Schizophrenia.

INTRODUCTION: Several nuclear receptor family members have been associated with schizophrenia and inflammation. Vitamins A and D exert anti-inflammatory actions, but their receptors (mainly nuclear receptors) have not been extensively studied in either schizophrenia brains or in association with neuroinflammation. We examined the expression of vitamin A (RARs and RXRs) and vitamin D and protein disulphide-isomerase A3 (PDIA3) receptors, as well as nuclear orphan receptors (NR4As), in the context of elevated cytokine expression in the dorsolateral prefrontal cortex (DLPFC). METHODS: mRNA levels of nuclear receptors were measured in DLPFC tissues via RT-qPCR. ANCOVAs comparing high inflammation schizophrenia, low inflammation schizophrenia and low inflammation control groups were performed. RESULTS: RARG, RXRB, NR4A1 and NR4A3 transcripts showed significant differential expression across the three groups (ANCOVA p = 0.02-0.001). Post hoc testing revealed significant reductions in RARG expression in schizophrenia with low inflammation compared to schizophrenia with high inflammation and to controls, and RXRB mRNA was significantly reduced in schizophrenia with low inflammation compared to controls. NR4A1 and NR4A3 mRNAs were decreased in schizophrenia with high inflammation compared to schizophrenia with low inflammation, with NR4A1 also significantly different to controls. CONCLUSION: In schizophrenia, changes in nuclear receptor mRNA levels involved with mediating actions of vitamin A derivatives vary according to the inflammatory state of brains.

Increased constitutive activation of NF-κB p65 (RelA) in peripheral blood cells of patients with progressive multiple sclerosis.

The NF-κB signalling pathway plays an important role in controlling cellular immune responses, inflammation and apoptosis. In multiple sclerosis (MS), there is evidence of dysregulation of NF-κB signalling in patients with a relapsing-remitting disease course, but thus far there is little information on whether it is also dysregulated in patients with progressive disease. We hypothesised that patients with progressive MS would have more activation of NF-κB than relapsing-remitting MS patients. Using several different methods, we showed that there was more nuclear translocation of p65 in cells from progressive MS patients, particularly in T cells and monocytes. In addition, the amount of p65 translocated to the nucleus in cells of patients with progressive MS was not increased upon non-specific activation of the cells with the mitogen Con A. These results suggest that NF-κB dysregulation occurs in patients with progressive MS patients, as well as those with relapsing-remitting MS.

Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia.

OBJECTIVE: The glutathione (GSH) pathway is the main antioxidant system to protect against oxidative stress in the human brain. In this study, we tested whether molecular components of the GSH antioxidant system are changed in dorsolateral prefrontal cortex tissue from people with schizophrenia compared to controls. METHOD: The levels of total glutathione and reduced GSH were determined by fluorometric assay via quantifying thiols in extracts from frontal cortex of 68 people. Immunoblotting was used to measure levels of enzymes responsible for maintaining GSH, the glutamyl-cysteine ligase (GCL) catalytic subunit (GCLC) and the GSH peroxidase (GPx)-like protein ( n = 74). Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to measure GCLC messenger RNA (mRNA) expression. RESULTS: Both total glutathione ( t(66) = 2.467, p = 0.016) and reduced GSH ( t(66) = 3.001, p = 0.004) levels were significantly less in people with schizophrenia than in controls. However, there were no significant differences in either GCLC-like protein ( t(72) = -1.077, p = 0.285) or GCLC mRNA expression ( t(71) = -0.376, p = 0.708) between people with schizophrenia and control subjects. There was also no significant difference of GPx-like protein levels between schizophrenia and controls ( t(72) = -0.060, p = 0.952). Moreover, no significant correlations of putative confounding factors with GSH changes were detected. DISCUSSION: These results suggest that people with schizophrenia have impaired GSH antioxidant capacity, alongside normal levels of key regulatory proteins.